Nadia Alam, Erick Oskam, Patricia M Stassen, Pieternel van Exter, Peter M van de Ven, Harm R Haak, Frits Holleman, Arthur van Zanten, Hien van Leeuwen-Nguyen, Victor Bon, Bart A M Duineveld, Rishi S Nannan Panday, Mark H H Kramer, Prabath W B Nanayakkara, PHANTASi Trial Investigators and the ORCA (Onderzoeks Consortium Acute Geneeskunde) Research Consortium the Netherlands

In patients with varying severity of sepsis, EMS personnel training improved early recognition and care in the whole acute care chain. However, giving antibiotics in the ambulance did not lead to improved survival, regardless of illness severity.

Djillali Annane

The core temperature of most animals varies with ambient temperature, a phenomenon called poikilothermia. However, humans, like other mammals and birds, are homeothermic, meaning that they are able to keep their central temperature at 37°C with only small fluctuations of about 0·5°C.1 The hypothalamus regulates body temperature by controlling three main physiological responses: skin vasomotor tone, skeletal muscle tone and shivering, and sweating. Central temperature can be shifted outside the normal range by two mechanisms.

Vincent M Quinten, Matijs van Meurs, Jack JM Ligtenberg, Jan C ter Maaten

In the Lancet Respiratory Medicine, Nadia Alam and colleagues1 assessed prehospital administration of intravenous ceftriaxone 2000 mg in addition to usual care (fluid resuscitation and supplementary oxygen) in the ambulance for patients with suspected sepsis in the randomised controlled PHANTASi trial.1 Unfortunately, this early intervention did not lead to improved sepsis survival compared with patients receiving usual care alone. Fewer patients died in the study (8% across both arms) than was predicted (40%) based on epidemiological studies at the time of the trial design.

The Lancet Respiratory Medicine

Sepsis is a major cause of illness and death, but it is challenging to diagnose, particularly in the early stages. The global incidence of sepsis is estimated to be around 30 million episodes per year, with a high incidence in neonates and children accounting for around 3 million cases and 1·2 million cases per year, respectively. According to the UK Sepsis Trust, sepsis claims more lives per year in the UK than lung cancer, and more lives than bowel, breast, and prostate cancer combined. Complexity in the diagnosis of sepsis arises from the heterogeneity of this disorder—it can be caused by a wide range of pathogens acting on different organs.

Carolin Fleischmann-Struzek, David M Goldfarb, Peter Schlattmann, Luregn J Schlapbach, Konrad Reinhart, Niranjan Kissoon

The incidence of sepsis is highest in neonates and children, yet the global burden of sepsis in these age groups has not been assessed. We reviewed available evidence from observational epidemiological studies to estimate the global burden and mortality of sepsis in neonates and children. We did a systematic review and meta-analysis of studies reporting population-based sepsis incidence in neonates and children, published between 1979 and 2016. Our search yielded 1270 studies, 23 of which met the inclusion criteria; 16 were from high-income countries and seven from middle-income countries.

Johnson, Alistair E. W.; Aboab, Jerome; Raffa, Jesse D.; Pollard, Tom J.; Deliberato, Rodrigo O.; Celi, Leo A.; Stone, David J.

Objectives: To evaluate the relative validity of criteria for the identification of sepsis in an ICU database. Design: Retrospective cohort study of adult ICU admissions from 2008 to 2012. Setting: Tertiary teaching hospital in Boston, MA. Patients: Initial admission of all adult patients to noncardiac surgical ICUs. Interventions: Comparison of five different algorithms for retrospectively identifying sepsis, including the Sepsis-3 criteria. Measurements and Main Results: 11,791 of 23,620 ICU admissions (49.9%) met criteria for the study. Within this subgroup, 59.9% were suspected of infection on ICU admission, 75.2% of admissions had Sequential Organ Failure Assessment greater than or equal to 2, and 49.1% had both suspicion of infection and Sequential Organ Failure Assessment greater than or equal to 2 thereby meeting the Sepsis-3 criteria. The area under the receiver operator characteristic of Sequential Organ Failure Assessment (0.74) for hospital mortality was consistent with previous studies of the Sepsis-3 criteria. The Centers for Disease Control and Prevention, Angus, Martin, Centers for Medicare & Medicaid Services, and explicit coding methods for identifying sepsis revealed respective sepsis incidences of 31.9%, 28.6%, 14.7%, 11.0%, and 9.0%. In-hospital mortality increased with decreasing cohort size, ranging from 30.1% (explicit codes) to 14.5% (Sepsis-3 criteria). Agreement among the criteria was acceptable (Cronbach’s alpha, 0.40–0.62). Conclusions: The new organ dysfunction-based Sepsis-3 criteria have been proposed as a clinical method for identifying sepsis. These criteria identified a larger, less severely ill cohort than that identified by previously used administrative definitions. The Sepsis-3 criteria have several advantages over prior methods, including less susceptibility to coding practices changes, provision of temporal context, and possession of high construct validity. However, the Sepsis-3 criteria also present new challenges, especially when calculated retrospectively. Future studies on sepsis should recognize the differences in outcome incidence among identification methods and contextualize their findings according to the different cohorts identified. 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 grants R01-EB017205 and R01-GM104987. Drs. Johnson, Raffa, Pollard, and Celi received support for article research from the National Institutes of Health. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: aewj@mit.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Johnson, Alistair E. W.; Aboab, Jerome; Raffa, Jesse D.; Pollard, Tom J.; Deliberato, Rodrigo O.; Celi, Leo A.; Stone, David J.

Objectives: To evaluate the relative validity of criteria for the identification of sepsis in an ICU database. Design: Retrospective cohort study of adult ICU admissions from 2008 to 2012. Setting: Tertiary teaching hospital in Boston, MA. Patients: Initial admission of all adult patients to noncardiac surgical ICUs. Interventions: Comparison of five different algorithms for retrospectively identifying sepsis, including the Sepsis-3 criteria. Measurements and Main Results: 11,791 of 23,620 ICU admissions (49.9%) met criteria for the study. Within this subgroup, 59.9% were suspected of infection on ICU admission, 75.2% of admissions had Sequential Organ Failure Assessment greater than or equal to 2, and 49.1% had both suspicion of infection and Sequential Organ Failure Assessment greater than or equal to 2 thereby meeting the Sepsis-3 criteria. The area under the receiver operator characteristic of Sequential Organ Failure Assessment (0.74) for hospital mortality was consistent with previous studies of the Sepsis-3 criteria. The Centers for Disease Control and Prevention, Angus, Martin, Centers for Medicare & Medicaid Services, and explicit coding methods for identifying sepsis revealed respective sepsis incidences of 31.9%, 28.6%, 14.7%, 11.0%, and 9.0%. In-hospital mortality increased with decreasing cohort size, ranging from 30.1% (explicit codes) to 14.5% (Sepsis-3 criteria). Agreement among the criteria was acceptable (Cronbach’s alpha, 0.40–0.62). Conclusions: The new organ dysfunction-based Sepsis-3 criteria have been proposed as a clinical method for identifying sepsis. These criteria identified a larger, less severely ill cohort than that identified by previously used administrative definitions. The Sepsis-3 criteria have several advantages over prior methods, including less susceptibility to coding practices changes, provision of temporal context, and possession of high construct validity. However, the Sepsis-3 criteria also present new challenges, especially when calculated retrospectively. Future studies on sepsis should recognize the differences in outcome incidence among identification methods and contextualize their findings according to the different cohorts identified. 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 grants R01-EB017205 and R01-GM104987. Drs. Johnson, Raffa, Pollard, and Celi received support for article research from the National Institutes of Health. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: aewj@mit.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Johnson, Alistair E. W.; Aboab, Jerome; Raffa, Jesse D.; Pollard, Tom J.; Deliberato, Rodrigo O.; Celi, Leo A.; Stone, David J.

Objectives: To evaluate the relative validity of criteria for the identification of sepsis in an ICU database. Design: Retrospective cohort study of adult ICU admissions from 2008 to 2012. Setting: Tertiary teaching hospital in Boston, MA. Patients: Initial admission of all adult patients to noncardiac surgical ICUs. Interventions: Comparison of five different algorithms for retrospectively identifying sepsis, including the Sepsis-3 criteria. Measurements and Main Results: 11,791 of 23,620 ICU admissions (49.9%) met criteria for the study. Within this subgroup, 59.9% were suspected of infection on ICU admission, 75.2% of admissions had Sequential Organ Failure Assessment greater than or equal to 2, and 49.1% had both suspicion of infection and Sequential Organ Failure Assessment greater than or equal to 2 thereby meeting the Sepsis-3 criteria. The area under the receiver operator characteristic of Sequential Organ Failure Assessment (0.74) for hospital mortality was consistent with previous studies of the Sepsis-3 criteria. The Centers for Disease Control and Prevention, Angus, Martin, Centers for Medicare & Medicaid Services, and explicit coding methods for identifying sepsis revealed respective sepsis incidences of 31.9%, 28.6%, 14.7%, 11.0%, and 9.0%. In-hospital mortality increased with decreasing cohort size, ranging from 30.1% (explicit codes) to 14.5% (Sepsis-3 criteria). Agreement among the criteria was acceptable (Cronbach’s alpha, 0.40–0.62). Conclusions: The new organ dysfunction-based Sepsis-3 criteria have been proposed as a clinical method for identifying sepsis. These criteria identified a larger, less severely ill cohort than that identified by previously used administrative definitions. The Sepsis-3 criteria have several advantages over prior methods, including less susceptibility to coding practices changes, provision of temporal context, and possession of high construct validity. However, the Sepsis-3 criteria also present new challenges, especially when calculated retrospectively. Future studies on sepsis should recognize the differences in outcome incidence among identification methods and contextualize their findings according to the different cohorts identified. 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 grants R01-EB017205 and R01-GM104987. Drs. Johnson, Raffa, Pollard, and Celi received support for article research from the National Institutes of Health. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: aewj@mit.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Imaizumi, Takahiro; Matsuda, Naoyuki; Tomita, Kengo; Palikhe, Sailesh; Ohashi, Wakana; Hattori, Kohshi; Hattori, Yuichi

Objectives: Inflammation and apoptosis are decisive mechanisms for the development of end-organ injury in sepsis. Activator protein-1 may play a key role in regulating expression of harmful genes responsible for the pathophysiology of septic end-organ injury along with the major transcription factor nuclear factor-κB. We investigated whether in vivo introduction of circular dumbbell activator protein-1 decoy oligodeoxynucleotides can provide benefits for reducing septic end-organ injury. Design: Laboratory and animal/cell research. Settings: University research laboratory. Subjects: Male BALB/c mice (8–10 wk old). Interventions: Activator protein-1 decoy oligodeoxynucleotides were effectively delivered into tissues of septic mice in vivo by preparing into a complex with atelocollagen given 1 hour after surgery. Materials and Main Results: Polymicrobial sepsis was induced by cecal ligation and puncture in mice. Activator protein-1 decoy oligodeoxynucleotide transfection inhibited abnormal production of proinflammatory and chemotactic cytokines after cecal ligation and puncture. Histopathologic changes in lung, liver, and kidney tissues after cecal ligation and puncture were improved by activator protein-1 decoy oligodeoxynucleotide administration. When activator protein-1 decoy oligodeoxynucleotides were given, apoptosis induction was strikingly suppressed in lungs, livers, kidneys, and spleens of cecal ligation and puncture mice. These beneficial effects of activator protein-1 decoy oligodeoxynucleotides led to a significant survival advantage in mice after cecal ligation and puncture. Apoptotic gene profiling indicated that activator protein-1 activation was involved in the up-regulation of many of proapoptotic and antiapoptotic genes in cecal ligation and puncture-induced sepsis. Conclusions: Our results indicate a detrimental role of activator protein-1 in the sepsis pathophysiology and the potential usefulness of activator protein-1 decoy oligodeoxynucleotides for the prevention and treatment of septic end-organ failure. 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 Grant-in-Aids for Scientific Research (20590250, 26460336) and for Challenging Exploratory Research (15K15661) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: nmatsuda@med.nagoya-u.ac.jp; yhattori@med.u-toyama.ac.jp Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Imaizumi, Takahiro; Matsuda, Naoyuki; Tomita, Kengo; Palikhe, Sailesh; Ohashi, Wakana; Hattori, Kohshi; Hattori, Yuichi

Objectives: Inflammation and apoptosis are decisive mechanisms for the development of end-organ injury in sepsis. Activator protein-1 may play a key role in regulating expression of harmful genes responsible for the pathophysiology of septic end-organ injury along with the major transcription factor nuclear factor-κB. We investigated whether in vivo introduction of circular dumbbell activator protein-1 decoy oligodeoxynucleotides can provide benefits for reducing septic end-organ injury. Design: Laboratory and animal/cell research. Settings: University research laboratory. Subjects: Male BALB/c mice (8–10 wk old). Interventions: Activator protein-1 decoy oligodeoxynucleotides were effectively delivered into tissues of septic mice in vivo by preparing into a complex with atelocollagen given 1 hour after surgery. Materials and Main Results: Polymicrobial sepsis was induced by cecal ligation and puncture in mice. Activator protein-1 decoy oligodeoxynucleotide transfection inhibited abnormal production of proinflammatory and chemotactic cytokines after cecal ligation and puncture. Histopathologic changes in lung, liver, and kidney tissues after cecal ligation and puncture were improved by activator protein-1 decoy oligodeoxynucleotide administration. When activator protein-1 decoy oligodeoxynucleotides were given, apoptosis induction was strikingly suppressed in lungs, livers, kidneys, and spleens of cecal ligation and puncture mice. These beneficial effects of activator protein-1 decoy oligodeoxynucleotides led to a significant survival advantage in mice after cecal ligation and puncture. Apoptotic gene profiling indicated that activator protein-1 activation was involved in the up-regulation of many of proapoptotic and antiapoptotic genes in cecal ligation and puncture-induced sepsis. Conclusions: Our results indicate a detrimental role of activator protein-1 in the sepsis pathophysiology and the potential usefulness of activator protein-1 decoy oligodeoxynucleotides for the prevention and treatment of septic end-organ failure. 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 Grant-in-Aids for Scientific Research (20590250, 26460336) and for Challenging Exploratory Research (15K15661) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: nmatsuda@med.nagoya-u.ac.jp; yhattori@med.u-toyama.ac.jp Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Imaizumi, Takahiro; Matsuda, Naoyuki; Tomita, Kengo; Palikhe, Sailesh; Ohashi, Wakana; Hattori, Kohshi; Hattori, Yuichi

Objectives: Inflammation and apoptosis are decisive mechanisms for the development of end-organ injury in sepsis. Activator protein-1 may play a key role in regulating expression of harmful genes responsible for the pathophysiology of septic end-organ injury along with the major transcription factor nuclear factor-κB. We investigated whether in vivo introduction of circular dumbbell activator protein-1 decoy oligodeoxynucleotides can provide benefits for reducing septic end-organ injury. Design: Laboratory and animal/cell research. Settings: University research laboratory. Subjects: Male BALB/c mice (8–10 wk old). Interventions: Activator protein-1 decoy oligodeoxynucleotides were effectively delivered into tissues of septic mice in vivo by preparing into a complex with atelocollagen given 1 hour after surgery. Materials and Main Results: Polymicrobial sepsis was induced by cecal ligation and puncture in mice. Activator protein-1 decoy oligodeoxynucleotide transfection inhibited abnormal production of proinflammatory and chemotactic cytokines after cecal ligation and puncture. Histopathologic changes in lung, liver, and kidney tissues after cecal ligation and puncture were improved by activator protein-1 decoy oligodeoxynucleotide administration. When activator protein-1 decoy oligodeoxynucleotides were given, apoptosis induction was strikingly suppressed in lungs, livers, kidneys, and spleens of cecal ligation and puncture mice. These beneficial effects of activator protein-1 decoy oligodeoxynucleotides led to a significant survival advantage in mice after cecal ligation and puncture. Apoptotic gene profiling indicated that activator protein-1 activation was involved in the up-regulation of many of proapoptotic and antiapoptotic genes in cecal ligation and puncture-induced sepsis. Conclusions: Our results indicate a detrimental role of activator protein-1 in the sepsis pathophysiology and the potential usefulness of activator protein-1 decoy oligodeoxynucleotides for the prevention and treatment of septic end-organ failure. 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 Grant-in-Aids for Scientific Research (20590250, 26460336) and for Challenging Exploratory Research (15K15661) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: nmatsuda@med.nagoya-u.ac.jp; yhattori@med.u-toyama.ac.jp Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Sepsis, which has been identified by the World Health Organization as a global health priority, has no proven pharmacologic treatment, other than the appropriate antibiotic agents, fluids, and vasopressors as needed; reported death rates among hospitalized patients range between 30% and 45%.……

Nemati, Shamim; Holder, Andre; Razmi, Fereshteh; Stanley, Matthew D.; Clifford, Gari D.; Buchman, Timothy G.

Objectives: Sepsis is among the leading causes of morbidity, mortality, and cost overruns in critically ill patients. Early intervention with antibiotics improves survival in septic patients. However, no clinically validated system exists for real-time prediction of sepsis onset. We aimed to develop and validate an Artificial Intelligence Sepsis Expert algorithm for early prediction of sepsis. Design: Observational cohort study. Setting: Academic medical center from January 2013 to December 2015. Patients: Over 31,000 admissions to the ICUs at two Emory University hospitals (development cohort), in addition to over 52,000 ICU patients from the publicly available Medical Information Mart for Intensive Care-III ICU database (validation cohort). Patients who met the Third International Consensus Definitions for Sepsis (Sepsis-3) prior to or within 4 hours of their ICU admission were excluded, resulting in roughly 27,000 and 42,000 patients within our development and validation cohorts, respectively. Interventions: None. Measurements and Main Results: High-resolution vital signs time series and electronic medical record data were extracted. A set of 65 features (variables) were calculated on hourly basis and passed to the Artificial Intelligence Sepsis Expert algorithm to predict onset of sepsis in the proceeding T hours (where T = 12, 8, 6, or 4). Artificial Intelligence Sepsis Expert was used to predict onset of sepsis in the proceeding T hours and to produce a list of the most significant contributing factors. For the 12-, 8-, 6-, and 4-hour ahead prediction of sepsis, Artificial Intelligence Sepsis Expert achieved area under the receiver operating characteristic in the range of 0.83–0.85. Performance of the Artificial Intelligence Sepsis Expert on the development and validation cohorts was indistinguishable. Conclusions: Using data available in the ICU in real-time, Artificial Intelligence Sepsis Expert can accurately predict the onset of sepsis in an ICU patient 4–12 hours prior to clinical recognition. A prospective study is necessary to determine the clinical utility of the proposed sepsis prediction model. The opinions or assertions contained herein are the private ones of the author/speaker and are not to be construed as official or reflecting the views of the Department of Defense, the Uniformed Services University of the Health Sciences, or any other agency of 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). Drs. Nemati, Stanley, and Clifford received support for article research from the National Institutes of Health (NIH). Dr. Nemati’s institution received funding from the NIH, award number K01ES025445. Dr. Holder received funding from CR Bard, Inc. Dr. Buchman’s institution received funding from the Henry M. Jackson Foundation for his role as site director in Surgical Critical Care Institute, www.sc2i.org, funded through the Department of Defense’s Health Program – Joint Program Committee 6/Combat Casualty Care (USUHS HT9404-13-1-0032 and HU0001-15-2-0001); from Society of Critical Care Medicine for his role as Editor-in-Chief of “Critical Care Medicine”; and from Philips Corporation (unrestricted educational grant to a physician education association in South Korea so he could present the results of his research in eICU). Dr. Buchman received support for article research from the Henry M Jackson Foundation. Ms. Ramzi has disclosed that she does not have any potential conflicts of interest. For information regarding this article, E-mail: shamim.nemati@alum.mit.edu Copyright © by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Nemati, Shamim; Holder, Andre; Razmi, Fereshteh; Stanley, Matthew D.; Clifford, Gari D.; Buchman, Timothy G.

Objectives: Sepsis is among the leading causes of morbidity, mortality, and cost overruns in critically ill patients. Early intervention with antibiotics improves survival in septic patients. However, no clinically validated system exists for real-time prediction of sepsis onset. We aimed to develop and validate an Artificial Intelligence Sepsis Expert algorithm for early prediction of sepsis. Design: Observational cohort study. Setting: Academic medical center from January 2013 to December 2015. Patients: Over 31,000 admissions to the ICUs at two Emory University hospitals (development cohort), in addition to over 52,000 ICU patients from the publicly available Medical Information Mart for Intensive Care-III ICU database (validation cohort). Patients who met the Third International Consensus Definitions for Sepsis (Sepsis-3) prior to or within 4 hours of their ICU admission were excluded, resulting in roughly 27,000 and 42,000 patients within our development and validation cohorts, respectively. Interventions: None. Measurements and Main Results: High-resolution vital signs time series and electronic medical record data were extracted. A set of 65 features (variables) were calculated on hourly basis and passed to the Artificial Intelligence Sepsis Expert algorithm to predict onset of sepsis in the proceeding T hours (where T = 12, 8, 6, or 4). Artificial Intelligence Sepsis Expert was used to predict onset of sepsis in the proceeding T hours and to produce a list of the most significant contributing factors. For the 12-, 8-, 6-, and 4-hour ahead prediction of sepsis, Artificial Intelligence Sepsis Expert achieved area under the receiver operating characteristic in the range of 0.83–0.85. Performance of the Artificial Intelligence Sepsis Expert on the development and validation cohorts was indistinguishable. Conclusions: Using data available in the ICU in real-time, Artificial Intelligence Sepsis Expert can accurately predict the onset of sepsis in an ICU patient 4–12 hours prior to clinical recognition. A prospective study is necessary to determine the clinical utility of the proposed sepsis prediction model. The opinions or assertions contained herein are the private ones of the author/speaker and are not to be construed as official or reflecting the views of the Department of Defense, the Uniformed Services University of the Health Sciences, or any other agency of 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). Drs. Nemati, Stanley, and Clifford received support for article research from the National Institutes of Health (NIH). Dr. Nemati’s institution received funding from the NIH, award number K01ES025445. Dr. Holder received funding from CR Bard, Inc. Dr. Buchman’s institution received funding from the Henry M. Jackson Foundation for his role as site director in Surgical Critical Care Institute, www.sc2i.org, funded through the Department of Defense’s Health Program – Joint Program Committee 6/Combat Casualty Care (USUHS HT9404-13-1-0032 and HU0001-15-2-0001); from Society of Critical Care Medicine for his role as Editor-in-Chief of “Critical Care Medicine”; and from Philips Corporation (unrestricted educational grant to a physician education association in South Korea so he could present the results of his research in eICU). Dr. Buchman received support for article research from the Henry M Jackson Foundation. Ms. Ramzi has disclosed that she does not have any potential conflicts of interest. For information regarding this article, E-mail: shamim.nemati@alum.mit.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Nemati, Shamim; Holder, Andre; Razmi, Fereshteh; Stanley, Matthew D.; Clifford, Gari D.; Buchman, Timothy G.

Objectives: Sepsis is among the leading causes of morbidity, mortality, and cost overruns in critically ill patients. Early intervention with antibiotics improves survival in septic patients. However, no clinically validated system exists for real-time prediction of sepsis onset. We aimed to develop and validate an Artificial Intelligence Sepsis Expert algorithm for early prediction of sepsis. Design: Observational cohort study. Setting: Academic medical center from January 2013 to December 2015. Patients: Over 31,000 admissions to the ICUs at two Emory University hospitals (development cohort), in addition to over 52,000 ICU patients from the publicly available Medical Information Mart for Intensive Care-III ICU database (validation cohort). Patients who met the Third International Consensus Definitions for Sepsis (Sepsis-3) prior to or within 4 hours of their ICU admission were excluded, resulting in roughly 27,000 and 42,000 patients within our development and validation cohorts, respectively. Interventions: None. Measurements and Main Results: High-resolution vital signs time series and electronic medical record data were extracted. A set of 65 features (variables) were calculated on hourly basis and passed to the Artificial Intelligence Sepsis Expert algorithm to predict onset of sepsis in the proceeding T hours (where T = 12, 8, 6, or 4). Artificial Intelligence Sepsis Expert was used to predict onset of sepsis in the proceeding T hours and to produce a list of the most significant contributing factors. For the 12-, 8-, 6-, and 4-hour ahead prediction of sepsis, Artificial Intelligence Sepsis Expert achieved area under the receiver operating characteristic in the range of 0.83–0.85. Performance of the Artificial Intelligence Sepsis Expert on the development and validation cohorts was indistinguishable. Conclusions: Using data available in the ICU in real-time, Artificial Intelligence Sepsis Expert can accurately predict the onset of sepsis in an ICU patient 4–12 hours prior to clinical recognition. A prospective study is necessary to determine the clinical utility of the proposed sepsis prediction model. The opinions or assertions contained herein are the private ones of the author/speaker and are not to be construed as official or reflecting the views of the Department of Defense, the Uniformed Services University of the Health Sciences, or any other agency of 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). Drs. Nemati, Stanley, and Clifford received support for article research from the National Institutes of Health (NIH). Dr. Nemati’s institution received funding from the NIH, award number K01ES025445. Dr. Holder received funding from CR Bard, Inc. Dr. Buchman’s institution received funding from the Henry M. Jackson Foundation for his role as site director in Surgical Critical Care Institute, www.sc2i.org, funded through the Department of Defense’s Health Program – Joint Program Committee 6/Combat Casualty Care (USUHS HT9404-13-1-0032 and HU0001-15-2-0001); from Society of Critical Care Medicine for his role as Editor-in-Chief of “Critical Care Medicine”; and from Philips Corporation (unrestricted educational grant to a physician education association in South Korea so he could present the results of his research in eICU). Dr. Buchman received support for article research from the Henry M Jackson Foundation. Ms. Ramzi has disclosed that she does not have any potential conflicts of interest. For information regarding this article, E-mail: shamim.nemati@alum.mit.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Roberts, Brian W.; Mohr, Nicholas M.; Ablordeppey, Enyo; Drewry, Anne M.; Ferguson, Ian T.; Trzeciak, Stephen; Kollef, Marin H.; Fuller, Brian M.

Objective: The objective of this study was to test the association between the partial pressure of arterial carbon dioxide and survival to hospital discharge among mechanically ventilated patients diagnosed with sepsis in the emergency department. Design: Retrospective cohort study of a single center trial registry. Setting: Academic medical center. Patients: Mechanically ventilated emergency department patients. Inclusion criteria: age 18 years and older, diagnosed with sepsis in the emergency department, and mechanical ventilation initiated in the emergency department. Interventions: Arterial blood gases obtained after initiation of mechanical ventilation were analyzed. The primary outcome was survival to hospital discharge. We tested the association between partial pressure of arterial carbon dioxide and survival using multivariable logistic regression adjusting for potential confounders. Sensitivity analyses, including propensity score matching were also performed. Measurements and Main Results: Six hundred subjects were included, and 429 (72%) survived to hospital discharge. The median (interquartile range) partial pressure of arterial carbon dioxide was 42 (34–53) mm Hg for the entire cohort and 44 (35–57) and 39 (31–45) mm Hg among survivors and nonsurvivors, respectively (p < 0.0001 Wilcox rank-sum test). On multivariable analysis, a 1 mm Hg rise in partial pressure of arterial carbon dioxide was associated with a 3% increase in odds of survival (adjusted odds ratio, 1.03; 95% CI, 1.01–1.04) after adjusting for tidal volume and other potential confounders. These results remained significant on all sensitivity analyses. Conclusion: In this sample of mechanically ventilated sepsis patients, we found an association between increasing levels of partial pressure of arterial carbon dioxide and survival to hospital discharge. These findings justify future studies to determine the optimal target partial pressure of arterial carbon dioxide range for mechanically ventilated sepsis patients. Clinical Trial Registration: ClinicalTrials.gov Identifier NCT02543554. Drs. Fuller and Roberts conceived the study. Mr. Ferguson and Dr. Fuller were responsible for acquisition and quality of the data. Dr. Roberts did the analysis. All authors were involved in interpretation of the data and participated in writing and revision of the article. Drs. Fuller and Roberts wrote the first and 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). B.M.F. and A.M.D. were funded by the KL2 Career Development Award, and this research was supported by the Washington University Institute of Clinical and Translational Sciences (Grants UL1 TR000448 and KL2 TR000450) from the National Center for Advancing Translational Sciences. B.M.F. was also funded by the Foundation for Barnes-Jewish Hospital Clinical and Translational Sciences Research Program (Grant # 8041–88). A.M.D. was also funded by the Foundation for Anesthesia Education and Research. N.M.M. was supported by grant funds from the Health Resources and Services Administration. E.A.A. was supported by Washington University School of Medicine Faculty grant and the Foundation for Barnes Jewish Hospital grant. M.H.K. was supported by the Barnes-Jewish Hospital Foundation. B.W.R. was supported by a grant from the National Institutes of Health/National Heart, Lung, and Blood Institute (K23HL126979). Drs. Roberts, Drewry, and Fuller received support for article research from National Institutes of Health (NIH). Dr. Roberts’ institution received funding from National Heart, Lung, and Blood Institute. Dr. Ablordeppey’s institution received funding from the Washington University School of Medicine and the Barnes Jewish Hospital Foundation. Dr. Drewry’s institution received funding from the NIH. Dr. Fuller’s institution received funding from the Foundation for Barnes-Jewish Hospital Clinical and Translational Sciences Research Program (Grant # 8041–88) and a KL2 Career Development Award, and this research was supported by the Washington University Institute of Clinical and Translational Sciences (Grants UL1 TR000448 and KL2 TR000450) from the National Center for Advancing Translational Sciences. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: roberts-brian-w@cooperhealth.edu Copyright © by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Roberts, Brian W.; Mohr, Nicholas M.; Ablordeppey, Enyo; Drewry, Anne M.; Ferguson, Ian T.; Trzeciak, Stephen; Kollef, Marin H.; Fuller, Brian M.

Objective: The objective of this study was to test the association between the partial pressure of arterial carbon dioxide and survival to hospital discharge among mechanically ventilated patients diagnosed with sepsis in the emergency department. Design: Retrospective cohort study of a single center trial registry. Setting: Academic medical center. Patients: Mechanically ventilated emergency department patients. Inclusion criteria: age 18 years and older, diagnosed with sepsis in the emergency department, and mechanical ventilation initiated in the emergency department. Interventions: Arterial blood gases obtained after initiation of mechanical ventilation were analyzed. The primary outcome was survival to hospital discharge. We tested the association between partial pressure of arterial carbon dioxide and survival using multivariable logistic regression adjusting for potential confounders. Sensitivity analyses, including propensity score matching were also performed. Measurements and Main Results: Six hundred subjects were included, and 429 (72%) survived to hospital discharge. The median (interquartile range) partial pressure of arterial carbon dioxide was 42 (34–53) mm Hg for the entire cohort and 44 (35–57) and 39 (31–45) mm Hg among survivors and nonsurvivors, respectively (p < 0.0001 Wilcox rank-sum test). On multivariable analysis, a 1 mm Hg rise in partial pressure of arterial carbon dioxide was associated with a 3% increase in odds of survival (adjusted odds ratio, 1.03; 95% CI, 1.01–1.04) after adjusting for tidal volume and other potential confounders. These results remained significant on all sensitivity analyses. Conclusion: In this sample of mechanically ventilated sepsis patients, we found an association between increasing levels of partial pressure of arterial carbon dioxide and survival to hospital discharge. These findings justify future studies to determine the optimal target partial pressure of arterial carbon dioxide range for mechanically ventilated sepsis patients. Clinical Trial Registration: ClinicalTrials.gov Identifier NCT02543554. Drs. Fuller and Roberts conceived the study. Mr. Ferguson and Dr. Fuller were responsible for acquisition and quality of the data. Dr. Roberts did the analysis. All authors were involved in interpretation of the data and participated in writing and revision of the article. Drs. Fuller and Roberts wrote the first and 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). B.M.F. and A.M.D. were funded by the KL2 Career Development Award, and this research was supported by the Washington University Institute of Clinical and Translational Sciences (Grants UL1 TR000448 and KL2 TR000450) from the National Center for Advancing Translational Sciences. B.M.F. was also funded by the Foundation for Barnes-Jewish Hospital Clinical and Translational Sciences Research Program (Grant # 8041–88). A.M.D. was also funded by the Foundation for Anesthesia Education and Research. N.M.M. was supported by grant funds from the Health Resources and Services Administration. E.A.A. was supported by Washington University School of Medicine Faculty grant and the Foundation for Barnes Jewish Hospital grant. M.H.K. was supported by the Barnes-Jewish Hospital Foundation. B.W.R. was supported by a grant from the National Institutes of Health/National Heart, Lung, and Blood Institute (K23HL126979). Drs. Roberts, Drewry, and Fuller received support for article research from National Institutes of Health (NIH). Dr. Roberts’ institution received funding from National Heart, Lung, and Blood Institute. Dr. Ablordeppey’s institution received funding from the Washington University School of Medicine and the Barnes Jewish Hospital Foundation. Dr. Drewry’s institution received funding from the NIH. Dr. Fuller’s institution received funding from the Foundation for Barnes-Jewish Hospital Clinical and Translational Sciences Research Program (Grant # 8041–88) and a KL2 Career Development Award, and this research was supported by the Washington University Institute of Clinical and Translational Sciences (Grants UL1 TR000448 and KL2 TR000450) from the National Center for Advancing Translational Sciences. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: roberts-brian-w@cooperhealth.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Suryadi N. N. Tatura, Elizabeth Clarissa Wowor, Jose M. Mandei, Rocky Wilar, Sarah M. Warouw, Johnny Rompis, Priscilla Kalensang and Joseph Tuda

Abstract. Severe congenital malaria associated with Plasmodium vivax is uncommon. In Indonesia, most congenital malaria cases are due to Plasmodium falciparum infections. Most cases of congenital or neonatal malaria in endemic areas are diagnosed from peripheral smear as part of routine sepsis workup. Differentiating congenital and acquired neonatal malaria is very difficult. The case presented in this study describes severe P. vivax malaria with cholestatic jaundice and sepsis-like signs and symptoms in neonates. The mother was asymptomatic and the neonate was successfully treated with intravenous artesunate. Severe P. vivax malaria with cholestatic jaundice in neonates is an uncommon condition that should be included in the differential diagnosis of infants displaying hemolytic anemia, thrombocytopenia, cholestatic jaundice, and hepatosplenomegaly in malaria-endemic zones. Early diagnosis can prevent the use of unnecessary antibiotics and mortality of neonates.

The American Journal of Tropical Medicine and Hygiene

Authors: Tatura SNN, Wowor EC, Mandei JM, Wilar R, Warouw SM, Rompis J, Kalensang P, Tuda J Abstract Severe congenital malaria associated with Plasmodium vivax is uncommon. In Indonesia, most congenital malaria cases are due to Plasmodium falciparum infections. Most cases of congenital or neonatal malaria in endemic areas are diagnosed from peripheral smear as part of routine sepsis workup. Differentiating congenital and acquired neonatal malaria is very difficult. The case presented in this study describes severe P. vivax malaria with cholestatic jaundice and sepsis-like signs and symptoms in neonates. The mother was asymptomatic and the neonate was successfully treated with intravenous artesunate. Severe P. vivax malaria with cholestatic jaundice in neonates is an uncommon condit...

Lai, Alison T.; Zeller, Michelle P.; Millen, Tina; Kavsak, Peter; Szczeklik, Wojciech; Elahie, Allahna; Alhazzani, Waleed; D’Aragon, Frederick; Jaeschke, Roman; Lamontagne, Francois; Karachi, Timothy; Cook, Deborah; Meade, Maureen; Rochwerg, Bram; on behalf of The Canadian Critical Care Trials Group

Objective: Use of hyperchloremic IV fluids for resuscitation in sepsis may be associated with increased mortality and use of renal replacement therapy. After crystalloids, 5% human albumin represents the second most common resuscitation fluid in the ICU. Its chloride concentration is rarely considered in the clinical setting. This study quantifies previously undocumented chloride concentrations of three 5% albumin solutions using biochemical analysis. Design: We performed blinded analysis of the electrolyte concentration of albumin samples obtained directly from the national blood supplier (Canadian Blood Services). Two-tailed independent t tests were performed for all possible comparative analyses. Analysis of variance testing was performed for relevant three-way comparisons. Significance threshold was set at p less than 0.05. Setting: All samples were analyzed in the core laboratory at an academic hospital associated with McMaster University in Hamilton, Ontario, Canada. Subjects: We analyzed 65 albumin samples from three available brands obtained through Canadian Blood Services. They include Plasbumin (n = 21), Alburex (n = 24), Octalbin (n = 20). Intervention: Laboratory technologists blinded to product identification measured the concentration of electrolytes, extended electrolytes, lactate, and albumin of each sample using the Abbott ARCHITECT c8000 chemistry analyzer. Measurements and Main Results: The mean chloride concentration of Plasbumin, Alburex, and Octalbin, respectively, were 109.4 mmol/L (SD, 1.3), 123.6 mmol/L (SD, 1.3), and 136.8 mmol/L (SD, 0.4). The mean sodium concentration of Plasbumin, Alburex, and Octalbin, respectively, were 139.6 mmol/L (SD, 1.6), 137.3 mmol/L (SD, 2.2), and 149.4 mmol/L (SD, 0.5). The chloride and sodium concentration differed significantly for all two-way comparisons (p < 0.0001) and multiple comparison testing (p < 0.0001). Conclusion: This study is the first to identify and document a statistically significant variability in the chloride concentration of available 5% albumin products. This study has also informed a pilot randomized controlled trial examining the effect of administering high chloride versus low chloride fluids in critically ill 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). Dr. Lai received funding from Hamilton Health Sciences Quality and Safety Grant. Dr. Zeller’s institution received funding from Hamilton Health Sciences Quality and Safety Grant; she received funding from Pfizer Advisory Board (unrelated to content of this article), and she disclosed she is a Medical Officer with Canadian Blood Services. Dr. Rochwerg’s institution received funding from McMaster University Department of Medicine Early Career Research Award. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: rochwerg@mcmaster.ca Copyright © by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Lai, Alison T.; Zeller, Michelle P.; Millen, Tina; Kavsak, Peter; Szczeklik, Wojciech; Elahie, Allahna; Alhazzani, Waleed; D’Aragon, Frederick; Jaeschke, Roman; Lamontagne, Francois; Karachi, Timothy; Cook, Deborah; Meade, Maureen; Rochwerg, Bram; on behalf of The Canadian Critical Care Trials Group

Objective: Use of hyperchloremic IV fluids for resuscitation in sepsis may be associated with increased mortality and use of renal replacement therapy. After crystalloids, 5% human albumin represents the second most common resuscitation fluid in the ICU. Its chloride concentration is rarely considered in the clinical setting. This study quantifies previously undocumented chloride concentrations of three 5% albumin solutions using biochemical analysis. Design: We performed blinded analysis of the electrolyte concentration of albumin samples obtained directly from the national blood supplier (Canadian Blood Services). Two-tailed independent t tests were performed for all possible comparative analyses. Analysis of variance testing was performed for relevant three-way comparisons. Significance threshold was set at p less than 0.05. Setting: All samples were analyzed in the core laboratory at an academic hospital associated with McMaster University in Hamilton, Ontario, Canada. Subjects: We analyzed 65 albumin samples from three available brands obtained through Canadian Blood Services. They include Plasbumin (n = 21), Alburex (n = 24), Octalbin (n = 20). Intervention: Laboratory technologists blinded to product identification measured the concentration of electrolytes, extended electrolytes, lactate, and albumin of each sample using the Abbott ARCHITECT c8000 chemistry analyzer. Measurements and Main Results: The mean chloride concentration of Plasbumin, Alburex, and Octalbin, respectively, were 109.4 mmol/L (SD, 1.3), 123.6 mmol/L (SD, 1.3), and 136.8 mmol/L (SD, 0.4). The mean sodium concentration of Plasbumin, Alburex, and Octalbin, respectively, were 139.6 mmol/L (SD, 1.6), 137.3 mmol/L (SD, 2.2), and 149.4 mmol/L (SD, 0.5). The chloride and sodium concentration differed significantly for all two-way comparisons (p < 0.0001) and multiple comparison testing (p < 0.0001). Conclusion: This study is the first to identify and document a statistically significant variability in the chloride concentration of available 5% albumin products. This study has also informed a pilot randomized controlled trial examining the effect of administering high chloride versus low chloride fluids in critically ill 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). Dr. Lai received funding from Hamilton Health Sciences Quality and Safety Grant. Dr. Zeller’s institution received funding from Hamilton Health Sciences Quality and Safety Grant; she received funding from Pfizer Advisory Board (unrelated to content of this article), and she disclosed she is a Medical Officer with Canadian Blood Services. Dr. Rochwerg’s institution received funding from McMaster University Department of Medicine Early Career Research Award. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: rochwerg@mcmaster.ca Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Lai, Alison T.; Zeller, Michelle P.; Millen, Tina; Kavsak, Peter; Szczeklik, Wojciech; Elahie, Allahna; Alhazzani, Waleed; D’Aragon, Frederick; Jaeschke, Roman; Lamontagne, Francois; Karachi, Timothy; Cook, Deborah; Meade, Maureen; Rochwerg, Bram; on behalf of The Canadian Critical Care Trials Group

Objective: Use of hyperchloremic IV fluids for resuscitation in sepsis may be associated with increased mortality and use of renal replacement therapy. After crystalloids, 5% human albumin represents the second most common resuscitation fluid in the ICU. Its chloride concentration is rarely considered in the clinical setting. This study quantifies previously undocumented chloride concentrations of three 5% albumin solutions using biochemical analysis. Design: We performed blinded analysis of the electrolyte concentration of albumin samples obtained directly from the national blood supplier (Canadian Blood Services). Two-tailed independent t tests were performed for all possible comparative analyses. Analysis of variance testing was performed for relevant three-way comparisons. Significance threshold was set at p less than 0.05. Setting: All samples were analyzed in the core laboratory at an academic hospital associated with McMaster University in Hamilton, Ontario, Canada. Subjects: We analyzed 65 albumin samples from three available brands obtained through Canadian Blood Services. They include Plasbumin (n = 21), Alburex (n = 24), Octalbin (n = 20). Intervention: Laboratory technologists blinded to product identification measured the concentration of electrolytes, extended electrolytes, lactate, and albumin of each sample using the Abbott ARCHITECT c8000 chemistry analyzer. Measurements and Main Results: The mean chloride concentration of Plasbumin, Alburex, and Octalbin, respectively, were 109.4 mmol/L (SD, 1.3), 123.6 mmol/L (SD, 1.3), and 136.8 mmol/L (SD, 0.4). The mean sodium concentration of Plasbumin, Alburex, and Octalbin, respectively, were 139.6 mmol/L (SD, 1.6), 137.3 mmol/L (SD, 2.2), and 149.4 mmol/L (SD, 0.5). The chloride and sodium concentration differed significantly for all two-way comparisons (p < 0.0001) and multiple comparison testing (p < 0.0001). Conclusion: This study is the first to identify and document a statistically significant variability in the chloride concentration of available 5% albumin products. This study has also informed a pilot randomized controlled trial examining the effect of administering high chloride versus low chloride fluids in critically ill 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). Dr. Lai received funding from Hamilton Health Sciences Quality and Safety Grant. Dr. Zeller’s institution received funding from Hamilton Health Sciences Quality and Safety Grant; she received funding from Pfizer Advisory Board (unrelated to content of this article), and she disclosed she is a Medical Officer with Canadian Blood Services. Dr. Rochwerg’s institution received funding from McMaster University Department of Medicine Early Career Research Award. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: rochwerg@mcmaster.ca Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Pidwill, G. R., Rego, S., Jenkinson, H. F., Lamont, R. J., Nobbs, A. H.

Group B Streptococcus (GBS) is a leading cause of neonatal sepsis, pneumonia and meningitis worldwide. In the majority of cases, GBS is transmitted vertically from mother to neonate, making maternal vaginal colonisation a key risk factor for neonatal disease. The fungus Candida albicans is an opportunistic pathogen of the female genitourinary tract, and the causative agent of vaginal thrush. Carriage of C. albicans has been shown to be an independent risk factor for vaginal colonisation by GBS. However, the nature of interactions between these two microbes is poorly understood. This study provides evidence of a reciprocal, synergistic interplay between GBS and C. albicans that may serve to promote their co-colonisation of the vaginal mucosa. GBS strains NEM316 (serotype III) and 515 (Ia) are shown to physically interact with C. albicans, with bacteria exhibiting tropism for candidal hyphal filaments. This interaction enhances association levels of both microbes with vaginal epithelial cell line VK2/E6E7. The ability of GBS to co-associate with C. albicans is dependent upon expression of hyphal-specific adhesin Als3. In turn, expression of GBS antigen I/II family adhesins (Bsp polypeptides) facilitates this co-association and confers upon surrogate Lactococcus lactis the capacity to exhibit enhanced interactions with C. albicans on vaginal epithelium. As genitourinary tract colonisation is an essential first step in the pathogenesis of GBS and C. albicans, the co-association mechanism reported here may have important implications for risk of disease involving both of these pathogens.

Yoon, Jaechul; Kym, Dohern; Hur, Jun; Kim, Youngmin; Yang, Hyeong-Tae; Yim, Haejun; Suk Cho, Yong; Chun, Wook

Objectives: We evaluated the ability of new sepsis (S3) criteria (compared with previous definitions of sepsis [S1] and burn sepsis criteria) to accurately determine the mortality in severe burns patients with sepsis. Design: This was retrospective cohort study. Setting: The Burn ICU of Burn Center, Hangang Sacred Heart Hospital, Hallym University, Seoul, Korea. Patients: A total of 1,185 adult patients (mean age, 49.1 yr) were admitted between January 2009 and December 2015. Interventions: The 1,185 patients enrolled in the present study and were then re-evaluated based on S1, burn sepsis, and S3 criteria, following which 565 patients, 812 patients, and 809 patients were diagnosed with sepsis based on S1, burn sepsis, S3 criteria, respectively. Measurements and Main Results: For diagnostic performance, sensitivity, specificity, predictive value, and likelihood ratio were calculated. The area under the curve of the receiver operating characteristic curve was calculated to determine the accuracy of mortality prediction. The optimal cutoff value of Sequential Organ Failure Assessment score was calculated by the decision tree method.Total body surface area burned was 33.4%. Patients were identified with sepsis using S1 (812), S3 (809), and burn sepsis (565) criteria. Overall mortality was 20.3%, highest (82.2%) and lowest (26.5%) occurred with new septic shock (SH3) and S3, respectively. The sensitivity and specificity for burn sepsis (84.6% and 61.8%) and SH3 (63.1% and 96.5%) were reported. Area under the curve values for Sequential Organ Failure Assessment scores were the highest in all sepsis categories. With Sequential Organ Failure Assessment score greater than or equal to 6 (with infection), the accuracy was 0.86 (95% CI, 0.82–0.89). Conclusions: The S3 criteria failed to show superior prognostic accuracy for mortality in severely burned patients. Sequential Organ Failure Assessment score greater than or equal to 6 may be a better criterion for the diagnosis of sepsis in burns patients. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: dohern@hallym.or.kr Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Pelton, S. I.

Despite advances in treatment and prevention, the pneumococcus continues as a dominant cause of severe pneumonia and sepsis, of otitis media, sinusitis and nonbacteremic pneumonia. Lewnard and colleagues use a unique data set of nasopharyngeal and middle ear fluid samples to provide further insight into the progression of nasopharyngeal pneumococcal colonization to disease. They report the comparative rate of progression from colonization to otitis media by serotype, providing insight as to how conjugate vaccines that do not reduce the overall presence of pneumococci in the nasopharynx dramatically impact the incidence of acute and complex otitis media.

Kuroda, Kosuke; Wake, Hidenori; Mori, Shuji; Hinotsu, Shiro; Nishibori, Masahiro; Morimatsu, Hiroshi

Objectives: Many biomarkers for sepsis are used in clinical practice; however, few have become the standard. We measured plasma histidine-rich glycoprotein levels in patients with systemic inflammatory response syndrome. We compared histidine-rich glycoprotein, procalcitonin, and presepsin levels to assess their significance as biomarkers. Design: Single-center, prospective, observational cohort study. Setting: ICU at an university-affiliated hospital. Patients: Seventy-nine ICU patients (70 with systemic inflammatory response syndrome and 9 without systemic inflammatory response syndrome) and 16 healthy volunteers. Interventions: None. Measurements and Main Results: We collected blood samples from patients within 24 hours of ICU admission. Histidine-rich glycoprotein levels were determined using enzyme-linked immunosorbent assay. The median histidine-rich glycoprotein level in healthy volunteers (n = 16) was 63.00 µg/mL (interquartile range, 51.53–66.21 µg/mL). Histidine-rich glycoprotein levels in systemic inflammatory response syndrome patients (n = 70; 28.72 µg/mL [15.74–41.46 µg/mL]) were lower than those in nonsystemic inflammatory response syndrome patients (n = 9; 38.64 µg/mL [30.26–51.81 µg/mL]; p = 0.049). Of 70 patients with systemic inflammatory response syndrome, 20 had sepsis. Histidine-rich glycoprotein levels were lower in septic patients than in noninfective systemic inflammatory response syndrome patients (8.71 µg/mL [6.72–15.74 µg/mL] vs 33.27 µg/mL [26.57–44.99 µg/mL]; p < 0.001) and were lower in nonsurvivors (n = 8) than in survivors (n = 62) of systemic inflammatory response syndrome (9.06 µg/mL [4.49–15.70 µg/mL] vs 31.78 µg/mL [18.57–42.11 µg/mL]; p < 0.001). Histidine-rich glycoprotein showed a high sensitivity and specificity for diagnosing sepsis. Receiver operating characteristic curve analysis for detecting sepsis within systemic inflammatory response syndrome patients showed that the area under the curve for histidine-rich glycoprotein, procalcitonin, and presepsin was 0.97, 0.82, and 0.77, respectively. In addition, survival analysis in systemic inflammatory response syndrome patients revealed that the Harrell C-index for histidine-rich glycoprotein, procalcitonin, and presepsin was 0.85, 0.65, and 0.87, respectively. Conclusions: Histidine-rich glycoprotein levels were low in patients with sepsis and were significantly related to mortality in systemic inflammatory response syndrome population. Furthermore, as a biomarker, histidine-rich glycoprotein may be superior to procalcitonin and presepsin. This study was conducted at Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. Drs. Kuroda and Wake contributed equally to this work. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by grants from Scientific Research from the Ministry of Health, Labour, and Welfare of Japan (WA2F2547, WA2F2601), the Japan Agency for Medical Research and Development, (AMED) (AMED 15lk0201014h0003), the Japan Society for the Promotion of Science (JSPS) (JSPS Number 2567046405, 15H0468617), and Secom Science and Technology Foundation (to Dr. Nishibori), and from the Hokuto Foundation for Bioscience (to Dr. Wake). Dr. Nishibori’s institution received funding from AMED in Japan and Secom Science and Technology Foundation, and he received support for article research from AMED in Japan and Secom Science and Technology Foundation. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: morima-h@md.okayama-u.ac.jp Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Kuroda, Kosuke; Wake, Hidenori; Mori, Shuji; Hinotsu, Shiro; Nishibori, Masahiro; Morimatsu, Hiroshi

Objectives: Many biomarkers for sepsis are used in clinical practice; however, few have become the standard. We measured plasma histidine-rich glycoprotein levels in patients with systemic inflammatory response syndrome. We compared histidine-rich glycoprotein, procalcitonin, and presepsin levels to assess their significance as biomarkers. Design: Single-center, prospective, observational cohort study. Setting: ICU at an university-affiliated hospital. Patients: Seventy-nine ICU patients (70 with systemic inflammatory response syndrome and 9 without systemic inflammatory response syndrome) and 16 healthy volunteers. Interventions: None. Measurements and Main Results: We collected blood samples from patients within 24 hours of ICU admission. Histidine-rich glycoprotein levels were determined using enzyme-linked immunosorbent assay. The median histidine-rich glycoprotein level in healthy volunteers (n = 16) was 63.00 µg/mL (interquartile range, 51.53–66.21 µg/mL). Histidine-rich glycoprotein levels in systemic inflammatory response syndrome patients (n = 70; 28.72 µg/mL [15.74–41.46 µg/mL]) were lower than those in nonsystemic inflammatory response syndrome patients (n = 9; 38.64 µg/mL [30.26–51.81 µg/mL]; p = 0.049). Of 70 patients with systemic inflammatory response syndrome, 20 had sepsis. Histidine-rich glycoprotein levels were lower in septic patients than in noninfective systemic inflammatory response syndrome patients (8.71 µg/mL [6.72–15.74 µg/mL] vs 33.27 µg/mL [26.57–44.99 µg/mL]; p < 0.001) and were lower in nonsurvivors (n = 8) than in survivors (n = 62) of systemic inflammatory response syndrome (9.06 µg/mL [4.49–15.70 µg/mL] vs 31.78 µg/mL [18.57–42.11 µg/mL]; p < 0.001). Histidine-rich glycoprotein showed a high sensitivity and specificity for diagnosing sepsis. Receiver operating characteristic curve analysis for detecting sepsis within systemic inflammatory response syndrome patients showed that the area under the curve for histidine-rich glycoprotein, procalcitonin, and presepsin was 0.97, 0.82, and 0.77, respectively. In addition, survival analysis in systemic inflammatory response syndrome patients revealed that the Harrell C-index for histidine-rich glycoprotein, procalcitonin, and presepsin was 0.85, 0.65, and 0.87, respectively. Conclusions: Histidine-rich glycoprotein levels were low in patients with sepsis and were significantly related to mortality in systemic inflammatory response syndrome population. Furthermore, as a biomarker, histidine-rich glycoprotein may be superior to procalcitonin and presepsin. This study was conducted at Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. Drs. Kuroda and Wake contributed equally to this work. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by grants from Scientific Research from the Ministry of Health, Labour, and Welfare of Japan (WA2F2547, WA2F2601), the Japan Agency for Medical Research and Development, (AMED) (AMED 15lk0201014h0003), the Japan Society for the Promotion of Science (JSPS) (JSPS Number 2567046405, 15H0468617), and Secom Science and Technology Foundation (to Dr. Nishibori), and from the Hokuto Foundation for Bioscience (to Dr. Wake). Dr. Nishibori’s institution received funding from AMED in Japan and Secom Science and Technology Foundation, and he received support for article research from AMED in Japan and Secom Science and Technology Foundation. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: morima-h@md.okayama-u.ac.jp Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Kuroda, Kosuke; Wake, Hidenori; Mori, Shuji; Hinotsu, Shiro; Nishibori, Masahiro; Morimatsu, Hiroshi

Objectives: Many biomarkers for sepsis are used in clinical practice; however, few have become the standard. We measured plasma histidine-rich glycoprotein levels in patients with systemic inflammatory response syndrome. We compared histidine-rich glycoprotein, procalcitonin, and presepsin levels to assess their significance as biomarkers. Design: Single-center, prospective, observational cohort study. Setting: ICU at an university-affiliated hospital. Patients: Seventy-nine ICU patients (70 with systemic inflammatory response syndrome and 9 without systemic inflammatory response syndrome) and 16 healthy volunteers. Interventions: None. Measurements and Main Results: We collected blood samples from patients within 24 hours of ICU admission. Histidine-rich glycoprotein levels were determined using enzyme-linked immunosorbent assay. The median histidine-rich glycoprotein level in healthy volunteers (n = 16) was 63.00 µg/mL (interquartile range, 51.53–66.21 µg/mL). Histidine-rich glycoprotein levels in systemic inflammatory response syndrome patients (n = 70; 28.72 µg/mL [15.74–41.46 µg/mL]) were lower than those in nonsystemic inflammatory response syndrome patients (n = 9; 38.64 µg/mL [30.26–51.81 µg/mL]; p = 0.049). Of 70 patients with systemic inflammatory response syndrome, 20 had sepsis. Histidine-rich glycoprotein levels were lower in septic patients than in noninfective systemic inflammatory response syndrome patients (8.71 µg/mL [6.72–15.74 µg/mL] vs 33.27 µg/mL [26.57–44.99 µg/mL]; p < 0.001) and were lower in nonsurvivors (n = 8) than in survivors (n = 62) of systemic inflammatory response syndrome (9.06 µg/mL [4.49–15.70 µg/mL] vs 31.78 µg/mL [18.57–42.11 µg/mL]; p < 0.001). Histidine-rich glycoprotein showed a high sensitivity and specificity for diagnosing sepsis. Receiver operating characteristic curve analysis for detecting sepsis within systemic inflammatory response syndrome patients showed that the area under the curve for histidine-rich glycoprotein, procalcitonin, and presepsin was 0.97, 0.82, and 0.77, respectively. In addition, survival analysis in systemic inflammatory response syndrome patients revealed that the Harrell C-index for histidine-rich glycoprotein, procalcitonin, and presepsin was 0.85, 0.65, and 0.87, respectively. Conclusions: Histidine-rich glycoprotein levels were low in patients with sepsis and were significantly related to mortality in systemic inflammatory response syndrome population. Furthermore, as a biomarker, histidine-rich glycoprotein may be superior to procalcitonin and presepsin. This study was conducted at Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. Drs. Kuroda and Wake contributed equally to this work. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by grants from Scientific Research from the Ministry of Health, Labour, and Welfare of Japan (WA2F2547, WA2F2601), the Japan Agency for Medical Research and Development, (AMED) (AMED 15lk0201014h0003), the Japan Society for the Promotion of Science (JSPS) (JSPS Number 2567046405, 15H0468617), and Secom Science and Technology Foundation (to Dr. Nishibori), and from the Hokuto Foundation for Bioscience (to Dr. Wake). Dr. Nishibori’s institution received funding from AMED in Japan and Secom Science and Technology Foundation, and he received support for article research from AMED in Japan and Secom Science and Technology Foundation. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: morima-h@md.okayama-u.ac.jp Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Pruinelli, Lisiane; Westra, Bonnie L.; Yadav, Pranjul; Hoff, Alexander; Steinbach, Michael; Kumar, Vipin; Delaney, Connie W.; Simon, Gyorgy

Objectives: To specify when delays of specific 3-hour bundle Surviving Sepsis Campaign guideline recommendations applied to severe sepsis or septic shock become harmful and impact mortality. Design: Retrospective cohort study. Setting: One health system composed of six hospitals and 45 clinics in a Midwest state from January 01, 2011, to July 31, 2015. Patients: All adult patients hospitalized with billing diagnosis of severe sepsis or septic shock. Interventions: Four 3-hour Surviving Sepsis Campaign guideline recommendations: 1) obtain blood culture before antibiotics, 2) obtain lactate level, 3) administer broad-spectrum antibiotics, and 4) administer 30 mL/kg of crystalloid fluid for hypotension (defined as “mean arterial pressure” < 65) or lactate (> 4). Measurements and Main Results: To determine the effect of t minutes of delay in carrying out each intervention, propensity score matching of “baseline” characteristics compensated for differences in health status. The average treatment effect in the treated computed as the average difference in outcomes between those treated after shorter versus longer delay. To estimate the uncertainty associated with the average treatment effect in the treated metric and to construct 95% CIs, bootstrap estimation with 1,000 replications was performed. From 5,072 patients with severe sepsis or septic shock, 1,412 (27.8%) had in-hospital mortality. The majority of patients had the four 3-hour bundle recommendations initiated within 3 hours. The statistically significant time in minutes after which a delay increased the risk of death for each recommendation was as follows: lactate, 20.0 minutes; blood culture, 50.0 minutes; crystalloids, 100.0 minutes; and antibiotic therapy, 125.0 minutes. Conclusions: The guideline recommendations showed that shorter delays indicates better outcomes. There was no evidence that 3 hours is safe; even very short delays adversely impact outcomes. Findings demonstrated a new approach to incorporate time t when analyzing the impact on outcomes and provide new evidence for clinical practice and research. The contents of this document are the sole responsibility of the authors and do not necessarily represent official views of the National Science Foundation/National Institutes of Health. Supported, in part, by National Science Foundation Grant number 1602394 and by the National Institutes of Health grant number GM120079. Drs. Westra, Kumar, and Simon received support for article research from the National Institutes of Health (NIH). Dr. Westra disclosed that this study is supported by National Science Foundation (NSF) grant IIS-1344135 and partially supported by Grant Number 1UL1RR033183 from the National Center for Research Resources of the NIH to the University of Minnesota Clinical and Translational Science Institute. Dr. Steinbach disclosed that he is supported, in part, by NSF and NIH grants and by the University of Minnesota, although no grants were received for this specific work. For this article, he received NSF-related funding. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: pruin001@umn.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Pruinelli, Lisiane; Westra, Bonnie L.; Yadav, Pranjul; Hoff, Alexander; Steinbach, Michael; Kumar, Vipin; Delaney, Connie W.; Simon, Gyorgy

Objectives: To specify when delays of specific 3-hour bundle Surviving Sepsis Campaign guideline recommendations applied to severe sepsis or septic shock become harmful and impact mortality. Design: Retrospective cohort study. Setting: One health system composed of six hospitals and 45 clinics in a Midwest state from January 01, 2011, to July 31, 2015. Patients: All adult patients hospitalized with billing diagnosis of severe sepsis or septic shock. Interventions: Four 3-hour Surviving Sepsis Campaign guideline recommendations: 1) obtain blood culture before antibiotics, 2) obtain lactate level, 3) administer broad-spectrum antibiotics, and 4) administer 30 mL/kg of crystalloid fluid for hypotension (defined as “mean arterial pressure” < 65) or lactate (> 4). Measurements and Main Results: To determine the effect of t minutes of delay in carrying out each intervention, propensity score matching of “baseline” characteristics compensated for differences in health status. The average treatment effect in the treated computed as the average difference in outcomes between those treated after shorter versus longer delay. To estimate the uncertainty associated with the average treatment effect in the treated metric and to construct 95% CIs, bootstrap estimation with 1,000 replications was performed. From 5,072 patients with severe sepsis or septic shock, 1,412 (27.8%) had in-hospital mortality. The majority of patients had the four 3-hour bundle recommendations initiated within 3 hours. The statistically significant time in minutes after which a delay increased the risk of death for each recommendation was as follows: lactate, 20.0 minutes; blood culture, 50.0 minutes; crystalloids, 100.0 minutes; and antibiotic therapy, 125.0 minutes. Conclusions: The guideline recommendations showed that shorter delays indicates better outcomes. There was no evidence that 3 hours is safe; even very short delays adversely impact outcomes. Findings demonstrated a new approach to incorporate time t when analyzing the impact on outcomes and provide new evidence for clinical practice and research. The contents of this document are the sole responsibility of the authors and do not necessarily represent official views of the National Science Foundation/National Institutes of Health. Supported, in part, by National Science Foundation Grant number 1602394 and by the National Institutes of Health grant number GM120079. Drs. Westra, Kumar, and Simon received support for article research from the National Institutes of Health (NIH). Dr. Westra disclosed that this study is supported by National Science Foundation (NSF) grant IIS-1344135 and partially supported by Grant Number 1UL1RR033183 from the National Center for Research Resources of the NIH to the University of Minnesota Clinical and Translational Science Institute. Dr. Steinbach disclosed that he is supported, in part, by NSF and NIH grants and by the University of Minnesota, although no grants were received for this specific work. For this article, he received NSF-related funding. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: pruin001@umn.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Pruinelli, Lisiane; Westra, Bonnie L.; Yadav, Pranjul; Hoff, Alexander; Steinbach, Michael; Kumar, Vipin; Delaney, Connie W.; Simon, Gyorgy

Objectives: To specify when delays of specific 3-hour bundle Surviving Sepsis Campaign guideline recommendations applied to severe sepsis or septic shock become harmful and impact mortality. Design: Retrospective cohort study. Setting: One health system composed of six hospitals and 45 clinics in a Midwest state from January 01, 2011, to July 31, 2015. Patients: All adult patients hospitalized with billing diagnosis of severe sepsis or septic shock. Interventions: Four 3-hour Surviving Sepsis Campaign guideline recommendations: 1) obtain blood culture before antibiotics, 2) obtain lactate level, 3) administer broad-spectrum antibiotics, and 4) administer 30 mL/kg of crystalloid fluid for hypotension (defined as “mean arterial pressure” < 65) or lactate (> 4). Measurements and Main Results: To determine the effect of t minutes of delay in carrying out each intervention, propensity score matching of “baseline” characteristics compensated for differences in health status. The average treatment effect in the treated computed as the average difference in outcomes between those treated after shorter versus longer delay. To estimate the uncertainty associated with the average treatment effect in the treated metric and to construct 95% CIs, bootstrap estimation with 1,000 replications was performed. From 5,072 patients with severe sepsis or septic shock, 1,412 (27.8%) had in-hospital mortality. The majority of patients had the four 3-hour bundle recommendations initiated within 3 hours. The statistically significant time in minutes after which a delay increased the risk of death for each recommendation was as follows: lactate, 20.0 minutes; blood culture, 50.0 minutes; crystalloids, 100.0 minutes; and antibiotic therapy, 125.0 minutes. Conclusions: The guideline recommendations showed that shorter delays indicates better outcomes. There was no evidence that 3 hours is safe; even very short delays adversely impact outcomes. Findings demonstrated a new approach to incorporate time t when analyzing the impact on outcomes and provide new evidence for clinical practice and research. The contents of this document are the sole responsibility of the authors and do not necessarily represent official views of the National Science Foundation/National Institutes of Health. Supported, in part, by National Science Foundation Grant number 1602394 and by the National Institutes of Health grant number GM120079. Drs. Westra, Kumar, and Simon received support for article research from the National Institutes of Health (NIH). Dr. Westra disclosed that this study is supported by National Science Foundation (NSF) grant IIS-1344135 and partially supported by Grant Number 1UL1RR033183 from the National Center for Research Resources of the NIH to the University of Minnesota Clinical and Translational Science Institute. Dr. Steinbach disclosed that he is supported, in part, by NSF and NIH grants and by the University of Minnesota, although no grants were received for this specific work. For this article, he received NSF-related funding. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: pruin001@umn.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Faisal, Muhammad; Scally, Andy; Richardson, Donald; Beatson, Kevin; Howes, Robin; Speed, Kevin; Mohammed, Mohammed A.

Objectives: To develop a logistic regression model to predict the risk of sepsis following emergency medical admission using the patient’s first, routinely collected, electronically recorded vital signs and blood test results and to validate this novel computer-aided risk of sepsis model, using data from another hospital. Design: Cross-sectional model development and external validation study reporting the C-statistic based on a validated optimized algorithm to identify sepsis and severe sepsis (including septic shock) from administrative hospital databases using International Classification of Diseases, 10th Edition, codes. Setting: Two acute hospitals (York Hospital - development data; Northern Lincolnshire and Goole Hospital - external validation data). Patients: Adult emergency medical admissions discharged over a 24-month period with vital signs and blood test results recorded at admission. Interventions: None. Main Results: The prevalence of sepsis and severe sepsis was lower in York Hospital (18.5% = 4,861/2,6247; 5.3% = 1,387/2,6247) than Northern Lincolnshire and Goole Hospital (25.1% = 7,773/30,996; 9.2% = 2,864/30,996). The mortality for sepsis (York Hospital: 14.5% = 704/4,861; Northern Lincolnshire and Goole Hospital: 11.6% = 899/7,773) was lower than the mortality for severe sepsis (York Hospital: 29.0% = 402/1,387; Northern Lincolnshire and Goole Hospital: 21.4% = 612/2,864). The C-statistic for computer-aided risk of sepsis in York Hospital (all sepsis 0.78; sepsis: 0.73; severe sepsis: 0.80) was similar in an external hospital setting (Northern Lincolnshire and Goole Hospital: all sepsis 0.79; sepsis: 0.70; severe sepsis: 0.81). A cutoff value of 0.2 gives reasonable performance. Conclusions: We have developed a novel, externally validated computer-aided risk of sepsis, with reasonably good performance for estimating the risk of sepsis for emergency medical admissions using the patient’s first, electronically recorded, vital signs and blood tests results. Since computer-aided risk of sepsis places no additional data collection burden on clinicians and is automated, it may now be carefully introduced and evaluated in hospitals with sufficient informatics infrastructure. Drs. Richardson and Mohammed had the original idea for this work. Dr. Faisal, Mr. Scally, and Dr. Mohammed undertook the statistical analyses. Mr. Beatson and Howes extracted the necessary data frames. Dr. Richardson gave a clinical perspective. Drs. Faisal and Mohammed wrote the first draft of this article, and all authors subsequently assisted in redrafting and have approved the final version. Dr. Mohammed will act as guarantor. 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, funded by the Health Foundation. The Health Foundation is an independent charity working to improve the quality of healthcare in the United Kingdom. This research was supported by the National Institute for Health Research (NIHR) Yorkshire and Humber Patient Safety Translational Research Centre (NIHR Yorkshire and Humber PSTRC). The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. All authors’ institutions received funding from the Health Foundation. Mr. Scally and Speed received support for article research from the Health Foundation. For information regarding this article, E-mail: M.A.Mohammed5@Bradford.ac.uk Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Faisal, Muhammad; Scally, Andy; Richardson, Donald; Beatson, Kevin; Howes, Robin; Speed, Kevin; Mohammed, Mohammed A.

Objectives: To develop a logistic regression model to predict the risk of sepsis following emergency medical admission using the patient’s first, routinely collected, electronically recorded vital signs and blood test results and to validate this novel computer-aided risk of sepsis model, using data from another hospital. Design: Cross-sectional model development and external validation study reporting the C-statistic based on a validated optimized algorithm to identify sepsis and severe sepsis (including septic shock) from administrative hospital databases using International Classification of Diseases, 10th Edition, codes. Setting: Two acute hospitals (York Hospital - development data; Northern Lincolnshire and Goole Hospital - external validation data). Patients: Adult emergency medical admissions discharged over a 24-month period with vital signs and blood test results recorded at admission. Interventions: None. Main Results: The prevalence of sepsis and severe sepsis was lower in York Hospital (18.5% = 4,861/2,6247; 5.3% = 1,387/2,6247) than Northern Lincolnshire and Goole Hospital (25.1% = 7,773/30,996; 9.2% = 2,864/30,996). The mortality for sepsis (York Hospital: 14.5% = 704/4,861; Northern Lincolnshire and Goole Hospital: 11.6% = 899/7,773) was lower than the mortality for severe sepsis (York Hospital: 29.0% = 402/1,387; Northern Lincolnshire and Goole Hospital: 21.4% = 612/2,864). The C-statistic for computer-aided risk of sepsis in York Hospital (all sepsis 0.78; sepsis: 0.73; severe sepsis: 0.80) was similar in an external hospital setting (Northern Lincolnshire and Goole Hospital: all sepsis 0.79; sepsis: 0.70; severe sepsis: 0.81). A cutoff value of 0.2 gives reasonable performance. Conclusions: We have developed a novel, externally validated computer-aided risk of sepsis, with reasonably good performance for estimating the risk of sepsis for emergency medical admissions using the patient’s first, electronically recorded, vital signs and blood tests results. Since computer-aided risk of sepsis places no additional data collection burden on clinicians and is automated, it may now be carefully introduced and evaluated in hospitals with sufficient informatics infrastructure. Drs. Richardson and Mohammed had the original idea for this work. Dr. Faisal, Mr. Scally, and Dr. Mohammed undertook the statistical analyses. Mr. Beatson and Howes extracted the necessary data frames. Dr. Richardson gave a clinical perspective. Drs. Faisal and Mohammed wrote the first draft of this article, and all authors subsequently assisted in redrafting and have approved the final version. Dr. Mohammed will act as guarantor. 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, funded by the Health Foundation. The Health Foundation is an independent charity working to improve the quality of healthcare in the United Kingdom. This research was supported by the National Institute for Health Research (NIHR) Yorkshire and Humber Patient Safety Translational Research Centre (NIHR Yorkshire and Humber PSTRC). The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. All authors’ institutions received funding from the Health Foundation. Mr. Scally and Speed received support for article research from the Health Foundation. For information regarding this article, E-mail: M.A.Mohammed5@Bradford.ac.uk Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Skorup, Paul; Maudsdotter, Lisa; Tano, Eva; Lipcsey, Miklós; Castegren, Markus; Larsson, Anders; Sjölin, Jan

Objectives: To investigate the dynamics of antibiotic-induced endotoxin liberation and inflammatory response in vivo in a clinically relevant large animal intensive care sepsis model and whether the addition of an aminoglycoside to a β-lactam antibiotic affects these responses. Design: Prospective, placebo-controlled interventional experimental study. Setting: University research unit. Subjects: Thirty-six healthy pigs administered Escherichia coli as a 3-hour infusion. Interventions: After 2 hours, during E. coli infusion, the animals were exposed to cefuroxime alone, the combination of cefuroxime and tobramycin, or saline. Measurements and Main Results: Plasma endotoxin, interleukin-6, tumor necrosis factor-α, leucocytes, and organ dysfunction were recorded for 4 hours after antibiotic treatment, and differences to the values before treatment were calculated. In vitro experiments were performed to ascertain whether endotoxin is released during antibiotic-induced bacterial killing of this E. coli strain. Despite differences between the treatment arms in vitro, no differences in plasma endotoxin were observed in vivo. Antibiotic-treated animals demonstrated a higher interleukin-6 response (p < 0.001), greater leucocyte activation (p < 0.001), and more pronounced deterioration in pulmonary static compliance (p < 0.01) over time than controls. Animals treated with the combination showed a trend toward less inflammation. Conclusions: Treatment with antibiotics may elicit an increased inflammatory interleukin-6 response that is associated with leucocyte activation and pulmonary organ dysfunction. No observable differences were detected in plasma endotoxin concentrations. The reduction in cefuroxime-induced endotoxin release after the addition of an aminoglycoside in vitro could not be reproduced in this model. This study was performed at the Section for Clinical Research and at the Hedenstierna Laboratory, Uppsala University Hospital, Uppsala, Sweden. 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 R&D funds of Uppsala University and by the Olinder-Nielsen Family Fund for Research in Infectious Diseases. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail paul.skorup@medsci.uu.se Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Masse, Marie-Hélène; Richard, Marie Anne; D’Aragon, Frédérick; St-Arnaud, Charles; Mayette, Michael; Adhikari, Neill K. J.; Fraser, William; Carpentier, André; Palanchuck, Steven; Gauthier, David; Lanthier, Luc; Touchette, Matthieu; Lamontagne, Albert; Chénard, Jean; Mehta, Sangeeta; Sansoucy, Yanick; Croteau, Etienne; Lepage, Martin; Lamontagne, François

Objectives: Mechanisms underlying sepsis-associated encephalopathy remain unclear, but reduced cerebral blood flow, alone or in conjunction with altered autoregulation, is reported as a potential contributor. We compared cerebral blood flow of control subjects and vasopressor-dependent septic patients. Design: Randomized crossover study. Setting: MRI with arterial spin labeling. Patients: Ten sedated septic patients on mechanical ventilation (four with controlled chronic hypertension) and 12 control subjects (six with controlled chronic hypertension) were enrolled. Mean ± SD ages were 61.4 ± 10.2 and 44.2 ± 12.8 years, respectively (p = 0.003). Mean Acute Physiology and Chronic Health Evaluation II score of septic patients at ICU admission was 27.7 ± 6.6. Interventions: To assess the potential confounding effects of sedation and mean arterial pressure, we measured cerebral blood flow with and without sedation with propofol in control subjects and at a target mean arterial pressure of 65 mm Hg and greater than or equal to 75 mm Hg in septic patients. The sequence of sedation versus no sedation and mean arterial pressure targets were randomized. Measurements and Main Results: In septic patients, cerebral blood flow measured at a mean arterial pressure target of 65 mm Hg (40.4 ± 10.9 mL/100 g/min) was not different from cerebral blood flow measured at a mean arterial pressure target of greater than or equal to 75 mm Hg (41.3 ± 9.8 mL/100 g/min; p = 0.65). In control subjects, we observed no difference in cerebral blood flow measured without and with sedation (24.8 ± 4.2 vs 24.9 ± 5.9 mL/100 g/min; p = 0.93). We found no interaction between chronic hypertension and the effect of sedation or mean arterial pressure targets. Cerebral blood flow measured in sedated septic patients (mean arterial pressure target 65 mm Hg) was 62% higher than in sedated control subjects (p = 0.001). Conclusions: In septic patients, cerebral blood flow was higher than in sedated control subjects and did not vary with mean arterial pressure targets. Further research is required to understand the clinical significance of cerebral hyperperfusion in septic patients on vasopressors and to reassess the neurologic effects of current mean arterial pressure targets in sepsis. This work was performed at Centre de recherche du CHUS, Sherbrooke, QC, Canada. Dr. F. Lamontagne conceived the study. Ms. Masse, Ms. Richard, and Drs. D’Aragon, Palanchuck, Lepage, and F. Lamontagne initiated the study design. Drs. St-Arnaud, Mayette, Adhikari, Fraser, Carpentier, Gauthier, Lanthier, Touchette, A. Lamontagne, Chénard, Mehta, Sansoucy, and Croteau helped with implementation. Drs. D’Aragon, Fraser, Carpentier, Sansoucy, Lepage, and F. Lamontagne are grant holders. Drs. Adhikari and F. Lamontagne provided statistical expertise in clinical trial design. All authors contributed to refinement of the study protocol and approved the final 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). Supported, in part, by grant from the Centre de Recherche du CHUS. Drs. D’Aragon, Fraser, Carpentier, Palanchuck, Gauthier, Croteau, Lepage, and F. Lamontagne members of the Fonds de recherche du Québec-Santé funded CRCHUS. Dr. Mayette received support for article research from local funding. Dr. Carpentier’s institution received funding for consulting from UniQure Biopharma, Siemens Healthcare/Molecular Imaging, and Janssen; for research grants from Merck Sharpe and Dome (UdeS), GlaxoSmithKline (chair), Janssen, UniQure Biopharma, Caprion (Canadian Institutes Health Research University of Toronto), and Jonhson & Jonhson; for invited speaker fees from Siemens Healthcare/Molecular Imaging, Merck, Amgen, UniQure, and Medtronic; for sponsored research from Hamilton Health Research, Novartis, AstraZeneca, BMS, Sanofi Aventis, Merck, Pfizer, NovoNordisk, The Medicine Companies, Exelixis, Amgen, and UniQure Biopharma; and for sponsorship for scientific events from Siemens, Amgen, Merck, Takeda, Pfizer, Agilent, Janssen, NovoNordisk, Boehringer Lilly, AstraZeneca, Sanofi, Amgen, Aegerion, and Financière Sun Life. Dr. Lepage received support for article research from pilot institutional funding. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: Francois.Lamontagne@USherbrooke.ca Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Sinha, M., Jupe, J., Mack, H., Coleman, T. P., Lawrence, S. M., Fraley, S. I.

SUMMARY Rapid and accurate profiling of infection-causing pathogens remains a significant challenge in modern health care. Despite advances in molecular diagnostic techniques, blood culture analysis remains the gold standard for diagnosing sepsis. However, this method is too slow and cumbersome to significantly influence the initial management of patients. The swift initiation of precise and targeted antibiotic therapies depends on the ability of a sepsis diagnostic test to capture clinically relevant organisms along with antimicrobial resistance within 1 to 3 h. The administration of appropriate, narrow-spectrum antibiotics demands that such a test be extremely sensitive with a high negative predictive value. In addition, it should utilize small sample volumes and detect polymicrobial infections and contaminants. All of this must be accomplished with a platform that is easily integrated into the clinical workflow. In this review, we outline the limitations of routine blood culture testing and discuss how emerging sepsis technologies are converging on the characteristics of the ideal sepsis diagnostic test. We include seven molecular technologies that have been validated on clinical blood specimens or mock samples using human blood. In addition, we discuss advances in machine learning technologies that use electronic medical record data to provide contextual evaluation support for clinical decision-making.

Mehta K, Im A, Rahman F, et al.

AbstractBackgroundPrior studies have shown that outcomes of hematopoietic stem cell transplantation (HSCT) in HIV (+) patients are similar to HIV (-) patients since effective implementation of HAART by 1998; but they are limited by small sample size or non-inclusion of recent data.MethodsWe queried National Inpatient Sample, a large inpatient dataset in the US, from 1998 to 2012 for HSCT using ICD9 procedure code 41.0. HIV patients were identified by ICD9 diagnostic code of 042, 043, 044, V08 and 079.53. Primary outcome was in-hospital mortality rate and secondary outcome was the in-hospital complication rate of HSCT. Outcomes were assessed by univariate, multivariate regression and matched-pair analysis.Results39,517 patients who underwent HSCT were identified. Among these, 108 patients had HIV. There were no differences in in-hospital mortality, intubation, sepsis, bacteremia, or graft vs host disease between HIV (+) and HIV (-) patients after allogeneic and autologous HSCT. In allogeneic HSCT, HIV (+) patients had significantly higher incidence of non-tuberculous mycobacteria and cytomegalovirus infection as compared to HIV (-) patients.ConclusionAlthough HIV (+) patients may have higher risk of certain opportunistic infections, they are not at higher risk of serious in-hospital complications of HSCT. Allogeneic and autologous HSCT can be safely performed in HIV (+) patients.

Papastamatiou, T., Routsias, J. G., Koutsoni, O., Dotsika, E., Tsakris, A., Spoulou, V.

Four previously identified immunodominant B-cell epitopes, located within known virulent pneumococcal proteins CbpD, PhtD, PhtE and ZmpB, had shown promising in vivo immunological characteristics indicating their potential to be used as vaccine antigens. In this study we further evaluated the opsonophagocytic activity of antibodies against these epitopes and their capacity to protect mice from pneumococcal sepsis. An Opsonophagocytic Killing Assay (OPKA) revealed that OPKA titers of human anti-peptide antibodies against Pneumococcal Serotypes 1, 3 and 19A were significantly higher (p…

Moffitt, K., Cheung, E., Manis, J., Malley, R.

Loss-of-function mutations in Signal Transducer and Activator of Transcription 3 gene (stat3) result in Autosomal Dominant Hyper IgE Syndrome (AD-HIES), a condition in which patients have recurrent debilitating infections, including frequent pneumococcal and staphylococcal pneumonias. Stat3 mutations cause defective adaptive TH17-cellular responses, an immune mechanism believed to be critical for clearance of pneumococcal colonization, and diminished antibody responses. Here we wished to evaluate the role of stat3 in clearance of pneumococcal carriage and immunity using mice with a stat3 mutation recapitulating AD-HIES. We show here that naïve AD-HIES mice have prolonged nasal carriage of pneumococcus compared to WT mice. Mutant and wild-type mice were then immunized with a pneumococcal whole cell vaccine (WCV) that provides TH-17-mediated protection against pneumococcal colonization and antibody-mediated protection against pneumonia and sepsis. WCV-immunized AD-HIES mice made significantly less pneumococcal-specific IL-17A and antibody compared to WT mice. WCV-elicited protection against colonization was abrogated in AD-HIES mice, but immunization with WCV still protected AD-HIES mice against aspiration pneumonia/sepsis. Taken together, our results suggest that impaired clearance of nasopharyngeal carriage due to poor adaptive IL-17A responses may contribute to the increased rates of pneumococcal respiratory infection in AD-HIES patients.

Deep, Akash; Sagar, Hiremath; Goonasekera, Chulananda; Karthikeyan, Palaniswamy; Brierley, Joe; Douiri, Abdel

Objectives: There are no studies in pediatrics evaluating the progression of acute kidney injury in septic shock. We investigated the evolution of sepsis-associated acute kidney injury and its association with systemic hemodynamics in children with fluid-refractory septic shock. Design: Prospective cohort study. Setting: PICU of a tertiary care hospital. Patients: All patients with fluid-refractory septic shock (n = 61) between September 2010 and February 2014. Interventions: Hemodynamic variables using noninvasive ultrasound cardiac output monitor were measured at admission and 6 hourly thereafter till 48 hours. We used the Kidney Disease: Improving Global Outcomes criteria to define and stage acute kidney injury. Associations between various hemodynamic variables and development of acute kidney injury were evaluated. Severe acute kidney injury was defined as stage 2 or 3 acute kidney injury and was compared with no acute kidney injury or stage 1 acute kidney injury. Measurements and Main Results: Severe acute kidney injury developed in 29.5% (n = 18) of the 61 children with fluid-refractory septic shock, whereas 43 patients (70.49%) had either no or stage 1 acute kidney injury. Most patients who developed acute kidney injury did so within the first 48 hours of PICU admission. Severe acute kidney injury conferred a three-fold increased risk of death by day 28 (hazard ratio, 3.23; 95% CI, 1.52–6.67; p = 0.002), longer ICU stay, and increased duration of mechanical ventilation. Central venous pressure at presentation was higher in severe acute kidney injury by 5 cm H2O. Highest lactate in the first 24 hours of PICU admission, low diastolic blood pressure, low systemic vascular resistance index at admission were associated with severe acute kidney injury. This model reliably predicted stage 2/3 acute kidney injury by day 3 with area under the curve equals to 94%; 95% CI, 88.3–99.99. None of the other hemodynamic variables showed any association with severe acute kidney injury. Conclusions: Manifestations of sepsis-associated acute kidney injury often occur early after PICU admission and is associated with increased morbidity and mortality. There is a need to develop a predictive model in septic shock which could facilitate early detection of acute kidney injury. This work was performed at King’s College Hospital, Denmark Hill, London SE5 9RS, United Kingdom. Ethical Statement: This was an observational study of routinely monitored hemodynamic and biochemical variables in the clinical management of children in septic shock in PICU and their outcomes. All children received standard therapies. Therefore, according to local guidelines, Ethics Committee review was not required. However, this study was registered as a service evaluation project at King’s College Hospital (Clinical Audit Support System project no. 2902). Dr. Deep is the supervisor who conceptualized the project and supervised data collection, interpretation and has reviewed and edited the article. He is the corresponding author. Drs. Sagar and Karthikeyan collected the data and contributed to the initial article. Drs. Goonasekera and Brierley helped edit the article. Dr. Douiri is senior lecturer of Biostatistics and Epidemiology in the department of primary care and public health sciences at King’s College London who advised the statistical design and analysis of the data. 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. Douiri acknowledges financial support from the National Institute for Health Research (NIHR) Biomedical Research and from the NIHR Collaboration for Leadership in Applied Health Research and Care South London at King’s College Hospital NHS Foundation Trust. The remaining authors have disclosed that they do not have any potential conflicts of interest. Address requests for reprints to: Akash Deep, MD, FRCPCH, PICU, King’s College Hospital, Denmark Hill, London SE5 9RS, United Kingdom. E-mail: akash.deep@nhs.net Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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

Theodoros Retsas, Klaus Huse, Lazaros-Dimitrios Lazaridis, Niki Karampela, Michael Bauer, Matthias Platzer, Virginia Kolonia, Eirini Papageorgiou, Evangelos J. Giamarellos-Bourboulis, George Dimopoulos

Liu, Vincent X.; Escobar, Gabriel J.; Chaudhary, Rakesh; Prescott, Hallie C.

Objectives: To quantify healthcare utilization in the week preceding sepsis hospitalization to identify potential opportunities to improve the recognition and treatment of sepsis prior to admission. Design: Retrospective study. Setting: Two large integrated healthcare delivery systems in the United States. Participants: Hospitalized sepsis patients. Interventions: None. Measurements and Main Results: We quantified clinician-based encounters in each of the 7 days preceding sepsis admission, as well as on the day of admission, and categorized them as: hospitalization, subacute nursing facility, emergency department, urgent care, primary care, and specialty care. We identified the proportion of encounters with diagnoses for acute infection based on 28 single-level Clinical Classification Software categories. We also quantified the use of antibiotics over the same interval and used linear regression to evaluate time trends. We included a total of 14,658 Kaiser Permanente Northern California sepsis hospitalizations and 31,369 Veterans Health Administration sepsis hospitalizations. Over 40% of patients in both cohorts required intensive care. A total of 7,747 Kaiser Permanente Northern California patients (52.9%) and 14,280 Veterans Health Administration patients (45.5%) were seen by a clinician in the week before sepsis. Prior to sepsis, utilization of subacute nursing facilities remained steady, whereas hospital utilization declined. Primary care, specialty care, and emergency department visits increased, particularly at admission day. Among those with a presepsis encounter, 2,648 Kaiser Permanente Northern California patients (34.2%) and 3,858 Veterans Health Administration patients (27.0%) had at least one acute infection diagnosis. An increasing percentage of outpatient encounters also had infectious diagnoses (3.3%/d; 95% CI, 1.5%–5.1%; p < 0.01), particularly in primary and specialty care settings. Prior to sepsis hospitalization, the use of antibiotics also increased steadily (2.1%/d; 95% CI, 1.1%–3.1%; p < 0.01). Conclusions: Over 45% of sepsis patients had clinician-based encounters in the week prior to hospitalization with an increasing frequency of diagnoses for acute infection and antibiotic use in the outpatient setting. These presepsis encounters offer several potential opportunities to improve the recognition, risk stratification, and treatment prior to sepsis hospitalization. Supported, in part, by funding from The Permanente Medical Group, IIR 11–109 from the U.S. Department of Veterans Affairs Health Services Research and Development Service, National Institutes of Health (NIH) K23GM112018 (to Dr. Liu), and NIH K08GM115859 (to Dr. Prescott). Drs. Liu, Escobar, and Prescott received support for article research from the National Institutes of Health (NIH). Dr. Liu’s institution received funding from the National Institute of General Medical Sciences. Dr. Escobar’s institution received funding from Gordon and Betty Moore Foundation (grants to develop predictive models for in-hospital deterioration and rehospitalization) and Merck (grant to develop predictive model for recurrent Clostridium difficile infection). Dr. Prescott’s institution received funding from the NIH, and she disclosed government work. Dr. Chaudhary disclosed that he does not have any potential conflicts of interest. For information regarding this article, E-mail: Vincent.X.Liu@kp.org Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Liu, Vincent X.; Escobar, Gabriel J.; Chaudhary, Rakesh; Prescott, Hallie C.

Objectives: To quantify healthcare utilization in the week preceding sepsis hospitalization to identify potential opportunities to improve the recognition and treatment of sepsis prior to admission. Design: Retrospective study. Setting: Two large integrated healthcare delivery systems in the United States. Participants: Hospitalized sepsis patients. Interventions: None. Measurements and Main Results: We quantified clinician-based encounters in each of the 7 days preceding sepsis admission, as well as on the day of admission, and categorized them as: hospitalization, subacute nursing facility, emergency department, urgent care, primary care, and specialty care. We identified the proportion of encounters with diagnoses for acute infection based on 28 single-level Clinical Classification Software categories. We also quantified the use of antibiotics over the same interval and used linear regression to evaluate time trends. We included a total of 14,658 Kaiser Permanente Northern California sepsis hospitalizations and 31,369 Veterans Health Administration sepsis hospitalizations. Over 40% of patients in both cohorts required intensive care. A total of 7,747 Kaiser Permanente Northern California patients (52.9%) and 14,280 Veterans Health Administration patients (45.5%) were seen by a clinician in the week before sepsis. Prior to sepsis, utilization of subacute nursing facilities remained steady, whereas hospital utilization declined. Primary care, specialty care, and emergency department visits increased, particularly at admission day. Among those with a presepsis encounter, 2,648 Kaiser Permanente Northern California patients (34.2%) and 3,858 Veterans Health Administration patients (27.0%) had at least one acute infection diagnosis. An increasing percentage of outpatient encounters also had infectious diagnoses (3.3%/d; 95% CI, 1.5%–5.1%; p < 0.01), particularly in primary and specialty care settings. Prior to sepsis hospitalization, the use of antibiotics also increased steadily (2.1%/d; 95% CI, 1.1%–3.1%; p < 0.01). Conclusions: Over 45% of sepsis patients had clinician-based encounters in the week prior to hospitalization with an increasing frequency of diagnoses for acute infection and antibiotic use in the outpatient setting. These presepsis encounters offer several potential opportunities to improve the recognition, risk stratification, and treatment prior to sepsis hospitalization. Supported, in part, by funding from The Permanente Medical Group, IIR 11–109 from the U.S. Department of Veterans Affairs Health Services Research and Development Service, National Institutes of Health (NIH) K23GM112018 (to Dr. Liu), and NIH K08GM115859 (to Dr. Prescott). Drs. Liu, Escobar, and Prescott received support for article research from the National Institutes of Health (NIH). Dr. Liu’s institution received funding from the National Institute of General Medical Sciences. Dr. Escobar’s institution received funding from Gordon and Betty Moore Foundation (grants to develop predictive models for in-hospital deterioration and rehospitalization) and Merck (grant to develop predictive model for recurrent Clostridium difficile infection). Dr. Prescott’s institution received funding from the NIH, and she disclosed government work. Dr. Chaudhary disclosed that he does not have any potential conflicts of interest. For information regarding this article, E-mail: Vincent.X.Liu@kp.org Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Liu, Vincent X.; Escobar, Gabriel J.; Chaudhary, Rakesh; Prescott, Hallie C.

Objectives: To quantify healthcare utilization in the week preceding sepsis hospitalization to identify potential opportunities to improve the recognition and treatment of sepsis prior to admission. Design: Retrospective study. Setting: Two large integrated healthcare delivery systems in the United States. Participants: Hospitalized sepsis patients. Interventions: None. Measurements and Main Results: We quantified clinician-based encounters in each of the 7 days preceding sepsis admission, as well as on the day of admission, and categorized them as: hospitalization, subacute nursing facility, emergency department, urgent care, primary care, and specialty care. We identified the proportion of encounters with diagnoses for acute infection based on 28 single-level Clinical Classification Software categories. We also quantified the use of antibiotics over the same interval and used linear regression to evaluate time trends. We included a total of 14,658 Kaiser Permanente Northern California sepsis hospitalizations and 31,369 Veterans Health Administration sepsis hospitalizations. Over 40% of patients in both cohorts required intensive care. A total of 7,747 Kaiser Permanente Northern California patients (52.9%) and 14,280 Veterans Health Administration patients (45.5%) were seen by a clinician in the week before sepsis. Prior to sepsis, utilization of subacute nursing facilities remained steady, whereas hospital utilization declined. Primary care, specialty care, and emergency department visits increased, particularly at admission day. Among those with a presepsis encounter, 2,648 Kaiser Permanente Northern California patients (34.2%) and 3,858 Veterans Health Administration patients (27.0%) had at least one acute infection diagnosis. An increasing percentage of outpatient encounters also had infectious diagnoses (3.3%/d; 95% CI, 1.5%–5.1%; p < 0.01), particularly in primary and specialty care settings. Prior to sepsis hospitalization, the use of antibiotics also increased steadily (2.1%/d; 95% CI, 1.1%–3.1%; p < 0.01). Conclusions: Over 45% of sepsis patients had clinician-based encounters in the week prior to hospitalization with an increasing frequency of diagnoses for acute infection and antibiotic use in the outpatient setting. These presepsis encounters offer several potential opportunities to improve the recognition, risk stratification, and treatment prior to sepsis hospitalization. Supported, in part, by funding from The Permanente Medical Group, IIR 11–109 from the U.S. Department of Veterans Affairs Health Services Research and Development Service, National Institutes of Health (NIH) K23GM112018 (to Dr. Liu), and NIH K08GM115859 (to Dr. Prescott). Drs. Liu, Escobar, and Prescott received support for article research from the National Institutes of Health (NIH). Dr. Liu’s institution received funding from the National Institute of General Medical Sciences. Dr. Escobar’s institution received funding from Gordon and Betty Moore Foundation (grants to develop predictive models for in-hospital deterioration and rehospitalization) and Merck (grant to develop predictive model for recurrent Clostridium difficile infection). Dr. Prescott’s institution received funding from the NIH, and she disclosed government work. Dr. Chaudhary disclosed that he does not have any potential conflicts of interest. For information regarding this article, E-mail: Vincent.X.Liu@kp.org Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Alexandra Peters, Sarah Masson-Roy, Didier Pittet

Taylor, Stephanie Parks; Karvetski, Colleen H.; Templin, Megan A.; Taylor, Brice T.

Objective: Evaluate racial disparities in sepsis processes of care. Design: Observational cohort study. Setting: Nine hospitals in the Southeastern United States between 2014 and 2016. Patients: Two thousand two hundred twenty-one white and 707 black patients treated in the emergency department through “code sepsis” pathway for suspected septic shock. Measurements and Main Results: Black patients were less likely to receive timely antibiotics than were white patients using multiple definitions (1 hr from code sepsis activation [odds ratio, 0.57; 95% CI, [0.44–0.74]; 85.6% vs. 91.2%; p < 0.0001]; 1 hr from triage [odds ratio, 0.83; 95% CI, [0.69–1.00]; 28.0% vs. 31.8%; p = 0.06]; 3 hr from triage [odds ratio, 0.71; 95% CI, [0.57–0.88]; 80.1% vs. 85.0%; p = 0.002]). Focusing on antibiotic administration within 1 hour of triage, these differences were enhanced after adjusting for patient-level factors (adjusted odds ratio, 0.80; 95% CI, [0.66–0.96]; p = 0.02), but attenuated after adjusting for hospital-level differences (adjusted odds ratio, 0.90; 95% CI, [0.81–1.01]; p = 0.07). Black and white patients did not differ on other sepsis quality indicators or adjusted mortality. Conclusions: Black patients appear to be less likely than white patients to receive timely antibiotic therapy for sepsis. These differences were largely explained by variation in care among hospitals, such that hospitals that disproportionately treat black patients were less likely to provide timely antibiotic therapy overall. There were no differences between races in other sepsis quality measures or adjusted mortality. 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: stephanie.p.taylor@carolinashealthcare.org Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Valley, Thomas S.; Nallamothu, Brahmajee K.; Heung, Michael; Iwashyna, Theodore J.; Cooke, Colin R.

Objectives: Acute renal replacement therapy in patients with sepsis has increased dramatically with substantial costs. However, the extent of variability in use across hospitals—and whether greater use is associated with better outcomes—is unknown. Design: Retrospective cohort study. Setting: Nationwide Inpatient Sample in 2011. Patients: Eighteen years old and older with sepsis and acute kidney injury admitted to hospitals sampled by the Nationwide Inpatient Sample in 2011. Interventions: We estimated the risk- and reliability-adjusted rate of acute renal replacement therapy use for patients with sepsis and acute kidney injury at each hospital. We examined the association between hospital-specific renal replacement therapy rate and in-hospital mortality and hospital costs after adjusting for patient and hospital characteristics. Measurements and Main Results: We identified 293,899 hospitalizations with sepsis and acute kidney injury at 440 hospitals, of which 6.4% (n = 18,885) received renal replacement therapy. After risk and reliability adjustment, the median hospital renal replacement therapy rate for patients with sepsis and acute kidney injury was 3.6% (interquartile range, 2.9–4.5%). However, hospitals in the top quintile of renal replacement therapy use had rates ranging from 4.8% to 13.4%. There was no significant association between hospital-specific renal replacement therapy rate and in-hospital mortality (odds ratio per 1% increase in renal replacement therapy rate: 1.03; 95% CI, 0.99–1.07; p = 0.10). Hospital costs were significantly higher with increasing renal replacement therapy rates (absolute cost increase per 1% increase in renal replacement therapy rate: $1,316; 95% CI, $157–$2,475; p = 0.03). Conclusions: Use of renal replacement therapy in sepsis varied widely among nationally sampled hospitals without associated differences in mortality. Improving renal replacement standards for the initiation of therapy for sepsis may reduce healthcare costs without increasing mortality. This article does not necessarily represent the views of the U.S. Government or the Department of Veterans Affairs. Dr. Valley had full access to all of the data in the study and takes full responsibility for the integrity of the data and the accuracy of the data analysis. Drs. Valley and Cooke contributed in study concept and design. Dr. Valley contributed in acquisition of data. Drs. Valley, Nallamothu, Heung, Iwashyna, and Cooke contributed in analysis and interpretation of data. Drs. Valley and Cooke contributed in drafting of the article. Drs. Valley, Nallamothu, Heung, Iwashyna, and Cooke contributed in critical revision of the article for important intellectual content. Drs. Valley and Cooke contributed in statistical analysis. Dr. Cooke obtained funding. 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 Institutes of Health T32HL007749 (to Dr. Valley), the Department of Veterans Affairs Health Services Research and Development Service grant 13–079 (to Dr. Iwashyna), and the Agency for Healthcare Research and Quality K08HS020672 (to Dr. Cooke). Dr. Valley received support for article research from the National Institutes of Health. Dr. Nallamothu received funding from United Healthcare and the American Heart Association. Dr. Iwashyna 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: valleyt@umich.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Septic shock is characterized by a dysregulated host response to infection, resulting in life-threatening circulatory, cellular, and metabolic abnormalities. The short-term mortality is approximately 45 to 50%, and 50% of survivors of sepsis may have subsequent long-term cognitive decline. Apart……

Murri R, Taccari F, Palazzolo C, et al.