Abstract Introduction Staphylococcus aureus frequently causes infections in outpatient and hospital settings and can present as a highly variable entity. Typical manifestations are endocarditis, osteoarticular infections or infection of implanted prostheses, intravascular devices or foreign bodies. A thorough diagnostic evaluation with early focus identification is mandatory to improve patient outcome. Case report We report a case of a 68-year old patient with a history of double allogeneic stem cell transplant for acute myeloid leukemia who developed a S. aureus bacteremia with dissemination, severe sepsis and lethal outcome due to nasal handkerchief packing after nose bleeding. Conclusion A thorough medical examination with further diagnostic work-up is most important in S. aureus blood stream infection to identify and eradicate the portal(s) of entry, to rule out endocarditis, to search for spinal abscesses, osteomyelitis or spondylodiscitis. Adherence to management guides for clinicians must be of major importance to achieve optimal quality of clinical care, and thus improve patient outcome.

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.

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.

Seilesh Kadambari, Heli Harvala, Peter Simmonds, Andrew J Pollard, Manish Sadarangani

Human parechovirus infections are the second most common cause of viral meningitis in children. These infections are most frequently seen in infants younger than 90 days. Clinical manifestations include encephalitis, meningitis, myocarditis, and sepsis, which can lead to serious neurodevelopmental sequelae in young infants. Molecular techniques, including PCR assays, are the preferred diagnostic methods and have contributed to an increase in reported cases, along with an increasing awareness of the causal role of human parechovirus in infant diseases.

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.

Maurizio Cecconi, Laura Evans, Mitchell Levy, Andrew Rhodes

Sepsis is a common condition that is associated with unacceptably high mortality and, for many of those who survive, long-term morbidity. Increased awareness of the condition resulting from ongoing campaigns and the evidence arising from research in the past 10 years have increased understanding of this problem among clinicians and lay people, and have led to improved outcomes. The World Health Assembly and WHO made sepsis a global health priority in 2017 and have adopted a resolution to improve the prevention, diagnosis, and management of sepsis.

Judith A Gilbert

Acute respiratory distress syndrome (ARDS) is a complex clinical condition in which pulmonary oedema—often secondary to pneumonia, sepsis, or trauma—leads to acute-onset hypoxaemia and respiratory failure. Globally, ARDS accounts for 10% of all intensive care unit admissions, and hospital mortality from ARDS ranges from 35% to 46% depending on severity. Numerous clinical trials have been done since ARDS was described in 1967, yet no pharmacological therapies have been found that improve outcomes for patients with ARDS; treatment is restricted to supportive care with mechanical ventilation as the cornerstone.

Paul E Marik

Glucocorticoids have been used as adjunctive therapy in patients with sepsis and septic shock for more than four decades. The rationale for the use of glucocorticoids is that this class of drugs downregulates the proinflammatory response and limits the anti-inflammatory response while preserving innate immunity. Between 1976 and 2017, 22 randomised placebo-controlled trials have been published evaluating the benefit of glucocorticoids in patients with community-acquired pneumonia, sepsis, and septic shock.

Ana Caroline N. Botelho, Juliana G. Oliveira, Andreia P. Damasco, Késia T. B. Santos, Ana Flávia M. Ferreira, Gabriel T. Rocha, Penélope S. Marinho, Rita B. G. Bornia, Tatiana C. A. Pinto, Marco A. Américo, Sergio E. L. Fracalanzza, Lúcia M. Teixeira

by Ana Caroline N. Botelho, Juliana G. Oliveira, Andreia P. Damasco, Késia T. B. Santos, Ana Flávia M. Ferreira, Gabriel T. Rocha, Penélope S. Marinho, Rita B. G. Bornia, Tatiana C. A. Pinto, Marco A. Américo, Sergio E. L. Fracalanzza, Lúcia M. Teixeira Group B Streptococcus (GBS) carriage by pregnant women is the primary risk factor for early-onset GBS neonatal sepsis. Intrapartum antibiotic prophylaxis (IAP) can prevent this transmission route, and two main approaches are recommended to base the selection of pregnant women to be submitted to IAP: the risk-based and the culture-based strategies. In Brazil, compliance to such recommendations is poor, and not much is known about GBS carriage. In the present study, 3,647 pregnant women living in Rio de Janeiro State, Brazil, were screened for GBS anogenital colonization, over a period of 8 years (2008–2015). GBS was detected in 956 (26.2%) of them, and presence of vaginal discharge was the only trait associated with a higher risk for GBS colonization. Serotypes Ia (257; 37.3%) and II (137; 19.9%) were the most frequent among 689 (72.1% of the total) GBS isolates evaluated, followed by NT isolates (84; 12.1%), serotype Ib (77; 11.1%), V (63; 9.1%), III (47; 6.8%) and IV (24; 3.5%). Estimated coverage of major serotype-based GBS vaccines currently under clinical trials would vary from 65.2% to 84.3%. All 689 isolates tested were susceptible to ampicillin and vancomycin. Resistance to chloramphenicol, clindamycin, erythromycin, levofloxacin, and tetracycline was observed in 5% (35), 2% (14), 14% (97), 5% (35) and 86% (592) of the isolates, respectively. No significant fluctuations in colonization rates, serotype distribution and antimicrobial susceptibility profiles were observed throughout the period of time investigated. The culture-based approach for IAP recommendation showed to be the best choice for the population investigated when compared to the risk-based, since the first did not increase the number of pregnant women submitted to antibiotic therapy and covered a larger number of women who were actually colonized by GBS. The fact the not all isolates were available for additional characterization, and serotype IX antiserum was not available for testing represent limitations of this study. Nevertheless, to the best of our knowledge, this is the largest investigation on GBS carriage among pregnant women in Brazil up to date, and results are useful for improving GBS prevention and treatment strategies.

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.

Ranzani, Otavio T.; Shankar-Hari, Manu; Harrison, David A.; Rabello, Lígia S.; Salluh, Jorge I. F.; Rowan, Kathryn M.; Soares, Marcio

Objectives: To test whether differences in both general and sepsis-specific patient characteristics explain the observed differences in sepsis mortality between countries, using two national critical care (ICU) databases. Design: Cohort study. Setting: We analyzed 62 and 164 ICUs in Brazil and England, respectively. Patients: Twenty-two–thousand four-hundred twenty-six adult ICU admissions from January 2013 to December 2013. Interventions: None. Measurements and Main Results: After harmonizing relevant variables, we merged the first ICU episode of adult medical admissions from Brazil (ORganizational CHaractEeriSTics in cRitical cAre study) and England (Intensive Care National Audit & Research Centre Case Mix Programme). Sepsis-3 definition was used, and the primary outcome was hospital mortality. We used multilevel logistic regression models to evaluate the impact of country (Brazil vs England) on mortality, after adjustment for general (age, sex, comorbidities, functional status, admission source, time to admission) and sepsis-specific (site of infection, organ dysfunction type and number) patient characteristics. Of medical ICU admissions, 13.2% (4,505/34,150) in Brazil and 30.7% (17,921/58,316) in England met the sepsis definition. The Brazil cohort was older, had greater prevalence of severe comorbidities and dependency compared with England. Respiratory was the most common infection site in both countries. The most common organ dysfunction was cardiovascular in Brazil (41.2%) and respiratory in England (85.8%). Crude hospital mortality was similar (Brazil 41.4% vs England 39.3%; odds ratio, 1.12 [0.98–1.30]). After adjusting for general patient characteristics, there was an important change in the point-estimate of the odds ratio (0.88 [0.75–1.02]). However, after adjusting for sepsis-specific patient characteristics, the direction of effect reversed again with Brazil having higher risk-adjusted mortality (odds ratio, 1.22 [1.05–1.43]). Conclusions: Patients with sepsis admitted to ICUs in Brazil and England have important differences in general and sepsis-specific characteristics, from source of admission to organ dysfunctions. We show that comparing crude mortality from sepsis patients admitted to the ICU between countries, as currently performed, is not reliable and that the adjustment for both general and sepsis-specific patient characteristics is essential for valid international comparisons of mortality amongst sepsis patients admitted to critical care units. Drs. Rowan and Soares are senior authors. † In memoriam. The views expressed in this publication are those of the author(s) and not necessarily those of the National Health Service, the National Institute for Health Research or the Department of Health. Drs. Ranzani and Shankar-Hari are equal contributors. Dr. Ranzani did data analyses. Drs. Ranzani and Shankar-Hari wrote the first draft of the article. Drs. Harrison, Rabello, Salluh, Rowan, and Soares led data collection. Dr. Rabello died during the peer-review process of this article. All authors unanimously agreed on her fundamental contribution for this study. All authors conceptualized and designed the study, interpreted data, and critically revised the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). The original ORganizational CHaractEeriSTics in cRitical cAre study was supported by the National Council for Scientific and Technological Development (Grant number 304240/2014-1), Carlos Chagas Filho Foundation for Research Support of the State of Rio de Janeiro and by departmental funds from the D’Or Institute for Research and Education. The Case Mix Programme is a subscription-based, national quality assessment program. The current study was funded internally by Intensive Care National Audit & Research Centre. The funding sources had no role in the design, conduct or analyses of the study. Dr. Shankar-Hari is supported by the National Institute for Health Research Clinician Scientist Award (NIHR-CS-2016-16-011). Dr. Soares disclosed that he is founder and equity shareholder at Epimed Solutions. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: otavioranzani@usp.br Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Abbasi J.

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

Sims, Charles R.; Warner, Matthew A.; Stelfox, Henry Thomas; Hyder, Joseph A.

Objectives: We examined recommendations within critical care guidelines to describe the pairing patterns for strength of recommendation and quality of evidence. We further identified recommendations where the reported strength of recommendation was strong while the reported quality of evidence was not high/moderate and then assessed whether such pairings were within five paradigmatic situations offered by Grading of Recommendations Assessment, Development and Evaluation methodology to justify such pairings. Data Sources and Extraction: We identified all clinical critical care guidelines published online from 2011 to 2017 by the Society of Critical Care Medicine along with individual guidelines published by Surviving Sepsis Campaign, Kidney Disease Improving Global Outcomes, American Society for Parenteral and Enteral Nutrition, and the Infectious Disease Society of America/American Thoracic Society. Data Synthesis: In all, 15 documents specifying 681 eligible recommendations demonstrated variation in strength of recommendation (strong n = 215 [31.6%], weak n = 345 [50.7%], none n = 121 [17.8%]) and in quality of evidence (high n = 41 [6.0%], moderate n = 151 [22.2%], low/very low n = 298 [43.8%], and Expert Consensus/none n = 191 [28.1%]). Strength of recommendation and quality of evidence were positively correlated (ρ = 0.66; p < 0.0001). Of 215 strong recommendations, 69 (32.1%) were discordantly paired with evidence other than high/moderate. Twenty-two of 69 (31.9%) involved Strong/Expert Consensus recommendations, a category discouraged by Grading of Recommendations Assessment, Development and Evaluation methodology. Forty-seven of 69 recommendations (68.1%) were comprised of Strong/Low or Strong/Very Low variation requiring justification within five paradigmatic scenarios. Among distribution in the five paradigmatic scenarios of Strong/Low and Strong/Very Low recommendations, the most common paradigmatic scenario was life threatening situation (n = 20/47; 42.6%). Four Strong/Low or Strong/Very Low recommendations (4/47; 8.5%) were outside Grading of Recommendations Assessment, Development and Evaluation methodology. Conclusions: Among a large, diverse assembly of critical care guideline recommendations using Grading of Recommendations Assessment, Development and Evaluation methodology, the strength of evidence of a recommendation was generally associated with the quality of evidence. However, strong recommendations were not infrequently made in the absence of high/moderate quality of evidence. To improve clarity and uptake, future guideline statements may specify why such pairings were made, avoid such pairings when outside of Grading of Recommendations Assessment, Development and Evaluation criteria, and consider separate language for Expert Consensus recommendations (good practice statements). 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 (httpm://journals.lww.com/ccmjournal). This work was performed without extramural funding. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: sims.charles@mayo.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Johnson J, Johnston B, Porter S, et al.

AbstractBackgroundThe distinguishing characteristics of extraintestinal pathogenic Escherichia coli (ExPEC) strains are incompletely defined.MethodsWe characterized 292 diverse-source human E. coli isolates (116 fecal, 27 cystitis, 30 pyelonephritis, 93 blood) for phylogenetic group, sequence type complex (STc), and 49 putative ExPEC-associated virulence genes. We then assessed these traits and ecological source as predictors of illness severity in a murine sepsis model.ResultsThe study isolates exhibited a broad range of virulence in mice. Most of the studied bacterial characteristics corresponded significantly with experimental virulence, as did ecological source and established molecular definitions of ExPEC and uropathogenic E. coli (UPEC). Multivariable modeling identified similar bacterial traits as independent predictors of illness severity both overall and among the fecal and clinical isolates separately: fyuA (yersiniabactin receptor), kpsM K1 (K1 capsule), and kpsM II (group 2 capsules). Molecular UPEC status predicted virulence independently only among fecal isolates. Neither ecological source (e.g., clinical vs. fecal) nor molecular ExPEC status added predictive power to these traits, which accounted collectively for up to 49% of observed virulence variation.ConclusionsAmong human-source E. coli isolates, specific accessory traits and phylogenetic/clonal backgrounds predict experimental virulence in a murine sepsis model better than does ecological source.

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.

Rowan, Courtney M.; McArthur, Jennifer; Hsing, Deyin D.; Gertz, Shira J.; Smith, Lincoln S.; Loomis, Ashley; Fitzgerald, Julie C.; Nitu, Mara E.; Moser, Elizabeth A. S.; Duncan, Christine N.; Mahadeo, Kris M.; Moffet, Jerelyn; Hall, Mark W.; Pinos, Emily L.; Tamburro, Robert F.; Cheifetz, Ira M.; for the Investigators of the Pediatric Acute Lung Injury and Sepsis Network

Objectives: Acute respiratory failure is common in pediatric hematopoietic cell transplant recipients and has a high mortality. However, respiratory prognostic markers have not been adequately evaluated for this population. Our objectives are to assess respiratory support strategies and indices of oxygenation and ventilation in pediatric allogeneic hematopoietic cell transplant patients receiving invasive mechanical ventilation and investigate how these strategies are associated with mortality. Design: Retrospective, multicenter investigation. Setting: Twelve U.S. pediatric centers. Patients: Pediatric allogeneic hematopoietic cell transplant recipients with respiratory failure. Interventions: None. Measurements and Main Results: Two-hundred twenty-two subjects were identified. PICU mortality was 60.4%. Nonsurvivors had higher peak oxygenation index (38.3 [21.3–57.6] vs 15.0 [7.0–30.7]; p < 0.0001) and oxygen saturation index (24.7 [13.8–38.7] vs 10.3 [4.6–21.6]; p < 0.0001), greater days with FIO2 greater than or equal to 0.6 (2.4 [1.0–8.5] vs 0.8 [0.3–1.6]; p < 0.0001), and more days with oxygenation index greater than 18 (1.4 [0–6.0] vs 0 [0–0.3]; p < 0.0001) and oxygen saturation index greater than 11 (2.0 [0.5–8.8] vs 0 [0–1.0]; p < 0.0001). Nonsurvivors had higher maximum peak inspiratory pressures (36.0 cm H2O [32.0–41.0 cm H2O] vs 30.0 cm H2O [27.0–35.0 cm H2O]; p < 0.0001) and more days with peak inspiratory pressure greater than 31 cm H2O (1.0 d [0–4.0 d] vs 0 d [0–1.0 d]; p < 0.0001). Tidal volume per kilogram was not different between survivors and nonsurvivors. Conclusions: In this cohort of pediatric hematopoietic cell transplant recipients with respiratory failure in the PICU, impaired oxygenation and use of elevated ventilator pressures were common and associated with increased mortality. This study was performed at the following institutions: Riley Hospital for Children at Indiana University School of Medicine; Joseph M. Sanzari Children’s Hospital at Hackensack University Medical Center; Medical College of Wisconsin, Children’s Hospital of Wisconsin; Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine; University of Minnesota, Masonic Children’s Hospital; Weil Cornell Medical College, New York Presbyterian Hospital; Dana-Farber Cancer Institute; Children’s Hospital of Los Angeles; University of Washington and Seattle Children’s Hospital; Duke Children’s Hospital; Nationwide Children’s Hospital; and Penn State Children’s Hospital. All authors participated in the development of the database and the study design for the presented article. All authors contributed to the data collection or review of the data. Dr. Rowan drafted the initial version of the article, and all contributing authors critically reviewed the article and contributed edits to be incorporated into the submitted version. Dr. Moser was responsible for the primary data analysis, but all contributing authors reviewed that analysis. All authors approved the final version of the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Ms. Moser’s institution received funding from Riley Riley Hospital for Children/Indiana University (a percentage of her salary as a biostatistician is funded by Pediatric Critical Care at Riley Hospital for Children/Indiana University in exchange for my professional services). Dr. Duncan received funding from Bluebird, Abgenomics, and Magenta Therapeautics. Dr. Tamburro’s institution received funding from the U.S. Federal Drug Administration Office of Orphan Products Development and Ony, Inc (provided surfactant free of charge for a clinical trial of calfactant among pediatric hematopoietic cell transplant patients with acute respiratory distress syndrome), and he received funding from Springer Publishing. Dr. Cheifetz received funding from Philips (medical adviser) and UptoDate (contributor).The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: coujohns@iu.edu 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%.……

Nubwa Medugu, Kenneth Iregbu, Pui-Ying Iroh Tam, Stephen Obaro

by Nubwa Medugu, Kenneth Iregbu, Pui-Ying Iroh Tam, Stephen Obaro Background Group B Streptococcus (GBS) causes invasive infections in neonates and has been implicated as a cause of prelabour rupture of membranes, preterm delivery and stillbirths. The success of phase II trials of polyvalent polysaccharide GBS vaccines indicates that these infections are potentially preventable. Nigeria is the most populous country in Africa with one of the highest birth rates, one of the highest neonatal sepsis incidence rates and one of the highest mortality rates in the world. Therefore, before the possible introduction of preventive strategies such as intrapartum antibiotic prophylaxis or GBS vaccine into Nigeria, it is vital that there is accurate data on the aetiology of neonatal sepsis and on the incidence of GBS neonatal sepsis in particular. The objective of this study was to determine the incidence and aetiology of neonatal sepsis in Nigeria with a focus on GBS sepsis and also to assess the potential impact of a GBS vaccine. Methods A literature search was conducted on the databases of African journals online, PubMed and Google Scholar for works conducted between 1987 to 2017. Case reports, reviews, and studies not stating specific culture methods or specific bacteria isolated were excluded. Data extracted included; incidence of neonatal sepsis, method of blood culture, blood volume, sample size, bacterial agents isolated and history of antibiotic use. PRISMA guidelines were followed and modified Down’s and Black criteria used to evaluate the quality of studies. Results A total of 5,114 studies were reviewed for neonatal sepsis out of which 24 consisting of a total of 2,280 cases were selected for final review. Nine studies met criteria for assessment of hospital based incidence of neonatal sepsis representing 31,305 hospital births. The incidence of neonatal sepsis was 18.2/1000 livebirths with range from 7-55/1000 livebirths while the GBS incidence was 0.06/1000 livebirths with range from 0-2/1000 live births. We discovered various limitations such as identification techniques that could result in underestimation of the true incidence of GBS sepsis. Pathogens such as Klebsiella pneumoniae and Staphylococcus aureus were more commonly isolated than GBS. Implications of key findings The hospital based incidence of neonatal sepsis was high at 18.2/1000 live births while that due to GBS was 0.06/1000 live births. The burden of neonatal sepsis, including that attributable to GBS is substantial and could be reduced by preventive strategies such as intrapartum antibiotic prophylaxis or GBS vaccine. There is however very sparse meaningful data currently. Well planned prospective studies with larger sample sizes, more advanced isolation and identification techniques and those following up invasive disease cases for possible short and long term sequelae are needed—not only prior to possible introduction of the vaccine to determine the baseline epidemiology, but also thereafter to monitor its impact on the population. Strategies need to be developed to also reduce the morbidity and mortality attributable to other bacteria that have an incidence even greater than that of GBS.

Mamta Jajoo, Vikas Manchanda, Suman Chaurasia, M. Jeeva Sankar, Hitender Gautam, Ramesh Agarwal, Chander Prakash Yadav, Kailash C. Aggarwal, Harish Chellani, Siddharth Ramji, Monorama Deb, Rajni Gaind, Surinder Kumar, Sugandha Arya, Vishnubhatla Sreenivas, Arti Kapil, Purva Mathur, Reeta Rasaily, Ashok K. Deorari, Vinod K. Paul, Investigators of the De lhi N eonatal I nfection S tudy (DeNIS) collaboration, New Delhi, India

by Mamta Jajoo, Vikas Manchanda, Suman Chaurasia, M. Jeeva Sankar, Hitender Gautam, Ramesh Agarwal, Chander Prakash Yadav, Kailash C. Aggarwal, Harish Chellani, Siddharth Ramji, Monorama Deb, Rajni Gaind, Surinder Kumar, Sugandha Arya, Vishnubhatla Sreenivas, Arti Kapil, Purva Mathur, Reeta Rasaily, Ashok K. Deorari, Vinod K. Paul, Investigators of the De lhi N eonatal I nfection S tudy (DeNIS) collaboration, New Delhi, India Background There is a paucity of data on the epidemiology of sepsis in outborn neonates being referred to level-3 units in low- and middle-income countries (LMIC). The objective of the present study was to evaluate the prevalence of sepsis and outcomes of outborn neonates with sepsis, and to characterize the pathogen profile and antimicrobial resistance (AMR) patterns of common isolates in them. Methods In this prospective observational cohort study (2011–2015), a dedicated research team enrolled all neonates admitted to an outborn level-3 neonatal unit and followed them until discharge/death. Sepsis work-up including blood culture(s) was performed upon suspicion of sepsis. All the isolates were identified and tested for antimicrobial susceptibility. Gram-negative pathogens resistant to any three of the five antibiotic classes (extended-spectrum cephalosporins, carbapenems, aminoglycosides, fluoroquinolones, and piperacillin-tazobactam) were labeled multi-drug resistant. Results Of the total of 2588 neonates enrolled, culture positive sepsis and total sepsis–i.e. culture positive and/or culture negative sepsis–was diagnosed in 13.1% (95% CI 11.8% to 14.5%) and 54.7% (95% CI 52.8% to 56.6%), respectively. The case fatality rates were 23.4% and 11.0% in culture-positive and total sepsis, respectively. Sepsis accounted for two-thirds of total neonatal deaths (153/235, 63.0%). Bacterial isolates caused about three-fourths (296/401; 73.8%) of the infections. The two common pathogens–Klebsiella pneumoniae (n = 50, 12.5%) and Acinetobacter baumannii (n = 46, 11.5%)–showed high degree of multi-drug resistance (78.0% and 91.3%, respectively) and carbapenem resistance (84.0% and 91.3%, respectively). About a quarter of infections were caused by Candida spp. (n = 91; 22.7%); almost three-fourths (73.7%) of these infections occurred in neonates born at or after 32 weeks’ gestation and about two-thirds (62.1%) in those weighing 1500 g or more at birth. Conclusions In this large outborn cohort, we report high burden of sepsis, high prevalence of systemic fungal infections, and alarming rates of antimicrobial resistance among bacterial pathogens.

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.

Barash, J. R., Castles, J. B., Arnon, S. S.

Infant botulism is an infectious intestinal toxemia that results from colonization of the infant large bowel by Clostridium botulinum (or rarely, by neurotoxigenic C. baratii or C. butyricum), with subsequent intraintestinal production and absorption of botulinum neurotoxin that then produces flaccid paralysis. The disease is often initially misdiagnosed as suspected sepsis or meningitis, diagnoses that require prompt empiric antimicrobial therapy. Antibiotics may also be needed to treat infectious complications of infant botulism, such as pneumonia or urinary tract infection. Clinical evidence suggests (see included case report) that broad-spectrum antibiotics that are eliminated by biliary excretion may cause progression of the patient’s paralysis by lysing C. botulinum vegetative cells in the large bowel lumen and thereby increasing the amount of botulinum neurotoxin available for absorption. The purpose of this antimicrobial susceptibility study was to identify an antimicrobial agent with little or no activity against C. botulinum that could be used to treat infant botulism patients initially diagnosed with suspected sepsis or meningitis, or who acquired secondary infections, without lysing C. botulinum. Testing of 12 antimicrobial agents indicated that almost all California infant botulism patient isolates are susceptible to most clinically utilized antibiotics and are also susceptible to newer antibiotics not previously tested against large numbers of C. botulinum patient isolates. No antibiotic with little or no activity against C. botulinum was identified. These findings reinforce the importance of promptly treating infant botulism patients with Human Botulism Immune Globulin (BIG-IV; BabyBIG®).

Hatfield, Kelly M.; Dantes, Raymund B.; Baggs, James; Sapiano, Mathew R. P.; Fiore, Anthony E.; Jernigan, John A.; Epstein, Lauren

Objectives: To assess the variability in short-term sepsis mortality by hospital among Centers for Medicare and Medicaid Services beneficiaries in the United States during 2013–2014. Design: A retrospective cohort design. Setting: Hospitalizations from 3,068 acute care hospitals that participated in the Centers for Medicare and Medicaid Services inpatient prospective payment system in 2013 and 2014. Patients: Medicare fee-for-service beneficiaries greater than or equal to 65 years old who had an inpatient hospitalization coded with present at admission severe sepsis or septic shock. Interventions: None. Measurements and Main Results: Individual level mortality was assessed as death at or within 7 days of hospital discharge and aggregated to calculate hospital-level mortality rates. We used a logistic hierarchal linear model to calculate mortality risk-adjusted for patient characteristics. We quantified variability among hospitals using the median odds ratio and calculated risk-standardized mortality rates for each hospital. The overall crude mortality rate was 34.7%. We found significant variability in mortality by hospital (p < 0.001). The middle 50% of hospitals had similar risk-standardized mortality rates (32.7–36.9%), whereas the decile of hospitals with the highest risk-standardized mortality rates had a median mortality rate of 40.7%, compared with a median of 29.2% for hospitals in the decile with the lowest risk-standardized mortality rates. The median odds ratio (1.29) was lower than the adjusted odds ratios for several measures of patient comorbidities and severity of illness, including present at admission organ dysfunction, no identified source of infection, and age. Conclusions: In a large study of present at admission sepsis among Medicare beneficiaries, we showed that mortality was most strongly associated with underlying comorbidities and measures of illness on arrival. However, after adjusting for patient characteristics, mortality also modestly depended on where a patient with sepsis received care, suggesting that efforts to improve sepsis outcomes in lower performing hospitals could impact sepsis survival. 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 salary funds at the Centers for Disease Control and Prevention. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Drs. Hatfield, Baggs, Sapiano, Fiore, Jernigan, and Epstein disclosed government work. Dr. Dantes disclosed that he does not have any potential conflicts of interest. For information regarding this article, E-mail: UYL3@cdc.gov 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.

Evans IR, Phillips GS, Alpern ER, et al.

This cohort study determines the risk-adjusted association between completing a 1-hour pediatric sepsis bundle and individual bundle elements with in-hospital mortality following statewide mandated care for pediatric sepsis in New York.

Rudd KE, Seymour CW, Aluisio AR, et al.

This pooled cohort analysis assesses the association of quick Sequential (Sepsis-Related Organ Failure Assessment (qSOFA) score with excess hospital death among patients with suspected infection in low- to middle-income countries and compares the mortality association using qSOFA vs systemic inflammatory response syndrome (SIRS) criteria.

Patel, A., Joseph, J., Periasamy, H., Mokale, S.

Sepsis is a life threatening systemic inflammatory condition triggered as a result of excessive host immune response to infection. In the past, immunomodulators have demonstrated protective effect in sepsis. Azithromycin (macrolide antibiotic) having immunomodulatory activity was therefore evaluated in combination with ceftriaxone in a clinically relevant murine model of sepsis induced by caecal ligation and puncture (CLP). First, mice underwent CLP and 3 h later were administered with vehicle or sub-protective dose of ceftriaxone (100 mg/kg, subcutaneous) alone or in combination with immunomodulatory dose of azithromycin (100 mg/kg, intraperitoneal). Survival was monitored for 5 days. In order to assess the immunomodulatory activity, parameters such as plasma and lung cytokines concentrations (interleukin IL-6, IL-1β, tumor necrosis factor-α), plasma glutathione (GSH), plasma and lung myeloperoxidase (MPO), body temperature, blood glucose, total white blood cell count, along with bacterial load in blood, peritoneal fluid and lung homogenate were measured 18 h after CLP challenge. Azithromycin in presence of ceftriaxone significantly improved the survival of CLP challenged mice. Further, the combination attenuated the elevated levels of inflammatory cytokines and MPO in plasma and lung tissue and increased the body temperature, blood glucose and GSH which were otherwise markedly decreased in CLP mice. Ceftriaxone exhibited significant reduction in bacterial load, while co-administration of azithromycin did not show further reduction. Therefore, the survival benefit by azithromycin was due to immunomodulation and not by its antibacterial action. Findings of this study indicate that azithromycin could provide clinical benefits in sepsis in conjunction with appropriate antibacterial agents.

Abiodun D. Ogunniyi, Zlatko Kopecki, Elizabeth E. Hickey, Manouchehr Khazandi, Emma Peel, Katherine Belov, Alexandra Boileau, Sanjay Garg, Henrietta Venter, Wei Yee Chan, Peter B. Hill, Stephen W. Page, Allison J. Cowin, Darren J. Trott

by Abiodun D. Ogunniyi, Zlatko Kopecki, Elizabeth E. Hickey, Manouchehr Khazandi, Emma Peel, Katherine Belov, Alexandra Boileau, Sanjay Garg, Henrietta Venter, Wei Yee Chan, Peter B. Hill, Stephen W. Page, Allison J. Cowin, Darren J. Trott There are very few articles in the literature describing continuous models of bacterial infections that mimic disease pathogenesis in humans and animals without using separate cohorts of animals at each stage of disease. In this work, we developed bioluminescent mouse models of partial-thickness scald wound infection and sepsis that mimic disease pathogenesis in humans and animals using a recombinant luciferase-expressing Staphylococcus aureus strain (Xen29). Two days post-scald wound infection, mice were treated twice daily with a 2% topical mupirocin ointment for 7 days. For sepsis experiments, mice were treated intraperitoneally with 6 mg/kg daptomycin 2 h and 6 h post-infection and time to moribund monitored for 72 h. Consistent bacterial burden data were obtained from individual mice by regular photon intensity quantification on a Xenogen IVIS Lumina XRMS Series III biophotonic imaging system, with concomitant significant reduction in photon intensities in drug-treated mice. Post-mortem histopathological examination of wounds and bacterial counts in blood correlated closely with disease severity and total flux obtained from Xen29. The bioluminescent murine models provide a refinement to existing techniques of multiple bacterial enumeration during disease pathogenesis and promote animal usage reduction. The models also provide an efficient and information-rich platform for preclinical efficacy evaluation of new drug classes for treating acute and chronic human and animal bacterial infections.

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

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

Vinci RJ, Melendez E.

Sepsis has been recognized by the United Nations World Health Assembly as a global threat to the health of children and adults. The World Health Organization has established as a priority the identification of strategies for prevention, early diagnosis, and treatment of sepsis.

Kidson, Kristen M.; Henderson, William R.; Hutcheon, Jennifer A.

Objectives: Case fatality in pregnancy-associated severe sepsis or septic shock appears reduced compared with nonpregnant women with severe sepsis or septic shock. It remains unclear if this difference is due to pregnancy or better baseline health status, among others. Our study compared adverse outcomes of pregnancy-associated severe sepsis or septic shock with nonpregnant women with severe sepsis or septic shock while controlling for age and chronic comorbidities. Design: Retrospective cohort study. Setting: Nationwide Inpatient Sample, a stratified sample of 20% acute care hospital admissions in the United States. Each entry includes patient and hospital characteristics as well as International Classification of Diseases, 9th revision, Clinical Modification, diagnoses and procedures. Subjects: Women of childbearing age (15–44 yr) with severe sepsis or septic shock–related hospitalizations during 1998–2012 identified using International Classification of Diseases, 9th revision, Clinical Modification, codes. Outcomes: Case fatality, hospital length of stay, length of stay until death, number of organ failures, rates of mechanical ventilation, and hemodialysis were compared in women according to pregnancy status, controlling for age, and chronic comorbidities. Measurements and Main Results: We identified 5,968 pregnancy-associated severe sepsis or septic shock and 85,240 nonpregnant women with severe sepsis or septic shock hospitalizations. Crude case fatality of pregnancy-associated severe sepsis or septic shock (9.6%) was lower than nonpregnant women with severe sepsis or septic shock (16.8%). The rate ratio for case fatality adjusted for socioeconomic status and race was 0.57 (95% CI, 0.52–0.62) while sequential adjustments for age and chronic comorbidities did not eliminate the association (rate ratio, 0.62 [95% CI, 0.57–0.68]) and 0.63 [95% CI, 0.57–0.68], respectively). Pregnancy-associated severe sepsis or septic shock was associated with shorter hospital length of stay (–0.83 d [95% CI, –1.32 to –0.34 d]), longer length of stay until death (2.61 d; [95% CI, 1.28–3.94 d]), and fewer organ failures (rate ratio, 0.95 [95% CI, 0.94–0.97]). Conclusions: Case fatality and adverse outcomes are reduced in women with pregnancy-associated severe sepsis or septic shock compared with nonpregnant women with severe sepsis or septic shock, and this is not explained by differences in age or chronic comorbidities alone. A less severe presentation of sepsis or protective effect of pregnancy may account for the difference observed with pregnancy-associated severe sepsis or septic shock. This work was performed at University of British Columbia. Ethics: This study was exempt from review by the University of British Columbia/British Columbia Children’s and Women’s Hospital Research Ethic Board as it used deidentified, publicly available data. Dr. Kidson was involved in the study concept, design, analysis, and interpretation of data, drafting the article, and critical review of the article. Dr. Henderson was responsible for study design, interpretation of data, and critical review of the article. Dr. Hutcheon was responsible for study design, data acquisition, analysis and interpretation of data, and critical review of the article. All authors approved the final version submitted for publication. 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: kmsokalski@alumni.ubc.ca 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...

Abraham, Mabel N.; Jimenez, Daniela M.; Fernandes, Tiago D.; Deutschman, Clifford S.

Objectives: Interventional trials on glucocorticoids in sepsis have yielded capricious results. Recent studies have identified multiple glucocorticoid receptor isoforms. The relative abundance of these isoforms in septic patients and following murine cecal ligation and puncture is unknown. The objective of this study is to determine the effects of cecal ligation and puncture on glucocorticoid receptor isoform abundance. Design: Determination of effects of cecal ligation and puncture on glucocorticoid receptor isoform subtype abundance in C57BL/6 mice. Examination of glucocorticoid receptor isoform abundance in tissues harvested from patients immediately after death from sepsis or nonseptic critical illness. Setting: Research laboratory. Subjects: C57BL/6 mice and human tissue sections from recently deceased critically ill patients. Interventions: C57BL/6 mice were subjected to cecal ligation and puncture or sham operation. Abundance of the activating glucocorticoid receptor α and the inactivating glucocorticoid receptor β isoforms was determined in mouse and human tissue using immunoblotting. Cardiac output with or without stimulation with dexamethasone was assessed using echocardiography. The expression of the gene encoding the glucocorticoid-dependent enzyme glucose-6-phosphatase was identified using polymerase chain reaction. Statistical significance (p < 0.05) was determined using analysis of variance. Measurements and Main Results: Results in baseline and sham operation mice were identical. At baseline, glucocorticoid receptor αA predominated in heart, lung, and skeletal muscle; abundance was decreased post cecal ligation and puncture. All glucocorticoid receptor α subtypes were identified in liver. Cecal ligation and puncture decreased the summed abundance of hepatic glucocorticoid receptor α subtypes and those of glucocorticoid receptors αA, B, and D. However, glucocorticoid receptor αC abundance was unchanged. Cecal ligation and puncture increased glucocorticoid receptor β protein abundance in the heart and lung. Relative to T0, cecal ligation and puncture decreased cardiac output and attenuated the cardiac output response to dexamethasone. Cecal ligation and puncture also decreased expression of glucose-6-phosphatase. Compared with nonseptic patients, human sepsis decreased the abundance of glucocorticoid receptor α and increased the abundance of glucocorticoid receptor β in heart and liver biopsies. Conclusions: Cecal ligation and puncture altered glucocorticoid receptor α and glucocorticoid receptor β isoform expression in tissues and decreased functional responses in heart and liver. Decreases in glucocorticoid receptor α and increases in glucocorticoid receptor β might explain the diminished glucocorticoid responsiveness observed in sepsis. Supported, in part, by National Institute of General Medical Sciences Grant R01GM121102 (to Dr. Deutschman). Dr. Deutschman received funding from the Society of Critical Care Medicine (travel and lodging for meetings of the Finance/Audit Committee, and honorarium as Scientific Editor for Critical Care Medicine), Englewood Medical Center (travel, honorarium for visiting lectureship), Johns Hopkins Medical Institutions for being the Safar Lecturer (travel, lodging, honorarium), American College of Chest Physicians (ACCP) (travel and honorarium as invited lecturer, annual meeting), Memorial Sloan Kettering Cancer Center (honorarium as visiting professor), Department of Anesthesiology at the University of West Virginia (travel, lodging, honorarium as visiting professor), Wiggers-Bernard Conference, Vienna, Austria (travel, lodging for participation), and Scientific Assembly, New Jersey Chapter of the ACCP (travel, honorarium for presentation). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: mabraham11@northwell.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Julio Collazos, Belén de la Fuente, Alicia García, Helena Gómez, C. Menéndez, Héctor Enríquez, Paula Sánchez, María Alonso, Ian López-Cruz, Manuel Martín-Regidor, Ana Martínez-Alonso, José Guerra, Arturo Artero, Marino Blanes, Javier de la Fuente, Víctor Asensi

by Julio Collazos, Belén de la Fuente, Alicia García, Helena Gómez, C. Menéndez, Héctor Enríquez, Paula Sánchez, María Alonso, Ian López-Cruz, Manuel Martín-Regidor, Ana Martínez-Alonso, José Guerra, Arturo Artero, Marino Blanes, Javier de la Fuente, Víctor Asensi Background Cellulitis is a frequent cause of hospital admission of adult patients. Increasing prevalence of multiresistant microorganisms, comorbidities, predisposing factors and medical and surgical therapies might affect cellulitis response and recurrence rate. Methods Prospective and observational study of 606 adult patients with cellulitis admitted to several Spanish hospitals. Comorbidities, microbiological, clinical, diagnostic, treatment (surgical and antibiotic) data were analyzed according to the cellulitis response. Good response implied cure. Poor response implied failure to cure or initial cure but relapse within 30 days of hospital discharge. Results Mean age was 63.3 years and 51.8% were men. Poor responses were significantly associated with age, previous episodes of cellulitis, prior wounds and skin lesions, venous insufficiency, lymphedema, immunosuppression and lower limbs involvement. No differences in ESR or CRP blood levels, leukocyte counts, pus or blood cultures positivity or microbiological or imaging aspects were observed in those with good or poor responses. Regarding antimicrobials, no differences in previous exposition before hospital admission, treatment with single or more than one antibiotic, antibiotic switch, days on antimicrobials or surgical treatment were observed regarding good or poor cellulitis response. Prior episodes of cellulitis (P = 0.0001), venous insufficiency (P = 0.004), immunosuppression (P = 0.03), and development of sepsis (P = 0.05) were associated with poor treatment responses, and non-surgical trauma (P = 0.015) with good responses, in the multivariate analysis. Conclusions Prior episodes of cellulitis, non-surgical trauma, venous insufficiency, sepsis and immunosuppression were independently associated with treatment response to cellulitis, but not the causative microorganism, the number of antimicrobials administered or its duration.

Joseph A. Hippensteel

American Journal of Respiratory and Critical Care Medicine, Volume 198, Issue 8, Page 981-983, October 15, 2018.

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.

Abstract To describe the characteristics of adult invasive H. influenzae disease, 34 patients diagnosed at a single tertiary center between 2004 and 2017 were analyzed in a retrospective case series study. The annual estimated incidence was 0.1 cases/100.000 inhabitants. Dominant source of infection was pneumonia accompanied by sepsis (62%) and caused by nontypeable strains (74%) with low ampicillin resistance (14%). Survival (94%) and complication rates were high (35%). Main empirical treatments were ceftriaxone or levofloxacine.

Abstract Background Sepsis-like illness with suspected meningitis or encephalitis is a common reason for using empiric antimicrobial therapy in infants and children. However, in cases of viral meningitis not covered by these antimicrobials, this management is ineffective and due to side effects potentially harmful. Methods A retrospective analysis of cerebrospinal fluid (CSF) multiplex PCRs (Biofire FilmArray®) in children with clinical suspicion of meningitis, encephalitis or sepsis-like illness was performed over the period of 1 year. Subsequently, a subgroup of children (age of 8–84 days of life) diagnosed with viral meningitis (enterovirus, HHV-6, human parechovirus) was compared to an age-matched control group. Results During the study period, the multiplex PCR panel was performed on 187 individual CSF samples that met the inclusion criteria. About half of the patients (92/187) were less than 1 year of age. In 27 cases (14.4%), the PCR yielded a positive result with the majority (12/27) being indicative of an enteroviral infection. In the age group of 8–84 days of life, 36.4% of the patients had a positive result. When the patients with a PCR positive for a viral agent were compared to an age-matched group of patients, no differences were observed regarding symptoms and laboratory parameters. However, the duration of antimicrobial therapy could be significantly reduced through the use of multiplex PCR. Conclusion The use of on-site diagnostic multiplex PCR was able to reduce the use of antimicrobials in selected cases. This test can guide clinical decisions earlier during the course of medical care compared to standard diagnostics.

Viriya Hantrakun, Ranjani Somayaji, Prapit Teparrukkul, Chaiyaporn Boonsri, Kristina Rudd, Nicholas P. J. Day, T. Eoin West, Direk Limmathurotsakul

by Viriya Hantrakun, Ranjani Somayaji, Prapit Teparrukkul, Chaiyaporn Boonsri, Kristina Rudd, Nicholas P. J. Day, T. Eoin West, Direk Limmathurotsakul Infection and sepsis are leading causes of death worldwide but the epidemiology and outcomes are not well understood in resource-limited settings. We conducted a four-year prospective observational study from March 2013 to February 2017 to examine the clinical epidemiology and outcomes of adults admitted with community-acquired infection in a resource-limited tertiary-care hospital in Ubon Ratchathani province, Northeast Thailand. Hospitalized patients with infection and accompanying systemic manifestations of infection within 24 hours of admission were enrolled. Subjects were classified as having sepsis if they had a modified sequential organ failure assessment (SOFA) score ≥2 at enrollment. This study was registered with ClinicalTrials.gov, number NCT02217592. A total of 4,989 patients were analyzed. Of the cohort, 2,659 (53%) were male and the median age was 57 years (range 18–101). Of these, 1,173 (24%) patients presented primarily to the study hospital, 3,524 (71%) were transferred from 25 district hospitals or 8 smaller hospitals in the province, and 292 (6%) were transferred from one of 30 hospitals in other provinces. Three thousand seven hundred and sixteen (74%) patients were classified as having sepsis. Patients with sepsis had an older age distribution and a greater prevalence of comorbidities compared to patients without sepsis. Twenty eight-day mortality was 21% (765/3,716) in sepsis and 4% (54/1,273) in non-sepsis patients (p

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.

Abstract Background Invasive candidiasis differs greatly between children and neonates. We aimed to investigate the different therapeutic approaches and their effects on treatment outcomes of these two groups. Methods Episodes of neonatal invasive candidiasis were compared with non-neonatal pediatric episodes during a 12-year cohort study. Clinical isolates were documented by matrix-assisted laser desorption/ionization-time of flight mass spectrometry and DNA sequencing, and antifungal susceptibility testing was performed. Results A total of 342 episodes of invasive candidiasis (113 neonatal and 229 non-neonatal pediatric episodes) in 281 pediatric patients (96 neonates and 185 children) were identified. Candida albicans was the most common pathogen causing invasive candidiasis in neonates and children (47.8% vs. 44.1%). The antifungal susceptibility profiles were not significantly different between neonates and children. More neonates received amphotericin B as therapy, whereas more children received fluconazole or caspofungin. Compared with children, neonates had a significantly longer duration of fungemia, higher rates of septic shock (34.5% vs. 21.8%; P = 0.013), sepsis-attributable mortality (28.3% vs. 17.5%; P = 0.024) and in-hospital mortality (42.7% vs. 25.4%; P = 0.004) than children. Independent risk factors for treatment failure of invasive candidiasis were septic shock (odds ration [OR] 16.01; 95% confidence interval [CI] 7.64–33.56; P 

Rhee, Chanu; Filbin, Michael R.; Massaro, Anthony F.; Bulger, Amy L.; McEachern, Donna; Tobin, Kathleen A.; Kitch, Barrett T.; Thurlo-Walsh, Bert; Kadar, Aran; Koffman, Alexandra; Pande, Anupam; Hamad, Yasir; Warren, David K.; Jones, Travis M.; O’Brien, Cara; Anderson, Deverick J.; Wang, Rui; Klompas, Michael; for the Centers for Disease Control and Prevention (CDC) Prevention Epicenters Program

Objectives: Many septic patients receive care that fails the Centers for Medicare and Medicaid Services’ SEP-1 measure, but it is unclear whether this reflects meaningful lapses in care, differences in clinical characteristics, or excessive rigidity of the “all-or-nothing” measure. We compared outcomes in cases that passed versus failed SEP-1 during the first 2 years after the measure was implemented. Design: Retrospective cohort study. Setting: Seven U.S. hospitals. Patients: Adult patients included in SEP-1 reporting between October 2015 and September 2017. Interventions: None. Measurements and Main Results: Of 851 sepsis cases in the cohort, 281 (33%) passed SEP-1 and 570 (67%) failed. SEP-1 failures had higher rates of septic shock (20% vs 9%; p < 0.001), hospital-onset sepsis (11% vs 4%; p = 0.001), and vague presenting symptoms (46% vs 30%; p < 0.001). The most common reasons for failure were omission of 3- and 6-hour lactate measurements (228/570 failures, 40%). Only 86 of 570 failures (15.1%) had greater than 3-hour delays until broad-spectrum antibiotics. Cases that failed SEP-1 had higher in-hospital mortality rates (18.4% vs 11.0%; odds ratio, 1.82; 95% CI, 1.19–2.80; p = 0.006), but this association was no longer significant after adjusting for differences in clinical characteristics and severity of illness (adjusted odds ratio, 1.36; 95% CI, 0.85–2.18; p = 0.205). Delays of greater than 3 hours until antibiotics were significantly associated with death (adjusted odds ratio, 1.94; 95% CI, 1.04–3.62; p = 0.038), whereas failing SEP-1 for any other reason was not (adjusted odds ratio, 1.10; 95% CI, 0.70–1.72; p = 0.674). Conclusions: Crude mortality rates were higher in sepsis cases that failed versus passed SEP-1, but there was no difference after adjusting for clinical characteristics and severity of illness. Delays in antibiotic administration were associated with higher mortality but only accounted for a small fraction of SEP-1 failures. SEP-1 may not clearly differentiate between high- and low-quality care, and detailed risk adjustment is necessary to properly interpret associations between SEP-1 compliance and mortality. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Centers for Disease Control and Prevention or the Agency for Healthcare Research and Quality. 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 Prevention Epicenters Program of the Centers for Disease Control and Prevention (grant number: U54CK000484) and the Agency for Healthcare Research and Quality (grant number: K08HS025008 to Dr. Rhee). Dr. Rhee’s institution received funding from the Centers for Disease Control and Prevention (CDC) and the Agency for Healthcare Research and Quality. Dr. Pande’s institution received funding from the CDC/National Institute for Communicable Diseases (NICD), and he received support for article research from the CDC/NICD. Dr. Hamad’s institution received a National Institutes of Health (NIH) grant for CDC center of excellence, and he received support for article research from the NIH. Dr. Warren received funding from consulting Worrell, Pursuit Vascular, and CareFusion/Becton Dickinson, as well as serving as a site subinvestigator for a vaccine trial sponsored by Pfizer. He received support for article research from the CDC Prevention Epicenters Program (U54CK000484). Dr. Jones’ institution received funding from the CDC Prevention Epicenters Program (U54CK000164). Drs. Anderson’s and Wang’s institutions received funding from the CDC. Dr. Anderson disclosed government work. Dr. Klompas’s institution received funding from the CDC and the Massachusetts Department of Public Health. The remaining authors have disclosed that they do not have any potential conflicts of interest. Presented in abstract form at the 2018 Society of Critical Care Medicine Conference (Abstract #1), San Antonio, TX, February 25, 2018. For information regarding this article, E-mail: crhee@bwh.harvard.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Jérôme Allyn, Cyril Ferdynus, Hugo Lo Pinto, Bruno Bouchet, Romain Persichini, David Vandroux, Berenice Puech, Nicolas Allou

by Jérôme Allyn, Cyril Ferdynus, Hugo Lo Pinto, Bruno Bouchet, Romain Persichini, David Vandroux, Berenice Puech, Nicolas Allou Background Treatment by venoarterial extracorporeal membrane oxygenation (VA-ECMO) is widely used today, even though it is associated with high risks of complications and death. While studies have focused on the relationship between some of these complications and the risk of death, the relationship between different complications has never been specifically examined, despite the fact that the occurrence of one complication is known to favor the occurrence of others. Our objective was to describe the relationship between complications in patients undergoing VA-ECMO in intensive care unit (ICU) and to identify, if possible, patterns of patients according to complications. Methods and findings As part of a retrospective cohort study, we conducted a multiple correspondence analysis followed by a hierarchical ascendant classification in order to identify patterns of patients according to main complications (sepsis, thromboembolic event, major transfusion, major bleeding, renal replacement therapy) and in-ICU death. Our cohort of 145 patients presented an in-ICU mortality rate of 50.3%. Morbidity was high, with 36.5% of patients presenting three or more of the five complications studied. Multiple correspondence analysis revealed a cumulative inertia of 76.9% for the first three dimensions. Complications were clustered together and clustered close to death, prompting the identification of four patterns of patients according to complications, including one with no complications. Conclusions Our study, based on a large cohort of patients undergoing VA-ECMO in ICU and presenting a mortality rate comparable to that reported in the literature, identified numerous and often interrelated complications. Multiple correspondence analysis and hierarchical ascendant classification yielded clusters of patients and highlighted specific links between some of the complications studied. Further research should be conducted in this area.

Marra, Annachiara; Pandharipande, Pratik P.; Girard, Timothy D.; Patel, Mayur B.; Hughes, Christopher G.; Jackson, James C.; Thompson, Jennifer L.; Chandrasekhar, Rameela; Ely, Eugene Wesley; Brummel, Nathan E.

Objectives: To describe the frequency of cooccurring newly acquired cognitive impairment, disability in activities of daily livings, and depression among survivors of a critical illness and to evaluate predictors of being free of post-intensive care syndrome problems. Design: Prospective cohort study. Setting: Medical and surgical ICUs from five U.S. centers. Patients: Patients with respiratory failure or shock, excluding those with preexisting cognitive impairment or disability in activities of daily livings. Interventions: None. Measurements and Main Results: At 3 and 12 months after hospital discharge, we assessed patients for cognitive impairment, disability, and depression. We categorized patients into eight groups reflecting combinations of cognitive, disability, and mental health problems. Using multivariable logistic regression, we modeled the association between age, education, frailty, durations of mechanical ventilation, delirium, and severe sepsis with the odds of being post-intensive care syndrome free. We analyzed 406 patients with a median age of 61 years and an Acute Physiology and Chronic Health Evaluation II of 23. At 3 and 12 months, one or more post-intensive care syndrome problems were present in 64% and 56%, respectively. Nevertheless, cooccurring post-intensive care syndrome problems (i.e., in two or more domains) were present in 25% at 3 months and 21% at 12 months. Post-intensive care syndrome problems in all three domains were present in only 6% at 3 months and 4% at 12 months. More years of education was associated with greater odds of being post-intensive care syndrome free (p < 0.001 at 3 and 12 mo). More severe frailty was associated with lower odds of being post-intensive care syndrome free (p = 0.005 at 3 mo and p = 0.048 at 12 mo). Conclusions: In this multicenter cohort study, one or more post-intensive care syndrome problems were present in the majority of survivors, but cooccurring problems were present in only one out of four. Education was protective from post-intensive care syndrome problems and frailty predictive of the development of post-intensive care syndrome problems. Future studies are needed to understand better the heterogeneous subtypes of post-intensive care syndrome and to identify modifiable risk factors. This work was performed at the Vanderbilt University Medical Center, Nashville, TN; Saint Thomas Hospital, Nashville, TN; Department of Veterans Affairs Medical Center, Tennessee Valley Healthsystem, Nashville, TN; Veterans Affairs Puget Sound Health Care System, Seattle, WA; and George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT. The contents of this article are solely the responsibility of the authors and do not necessarily represent those of the Department of Veterans Affairs, the National Institutes of Health, or Vanderbilt University Medical Center. Drs. Marra and Brummel had full access to all study data, take responsibility for the integrity of the data and the accuracy of the data analysis. Drs. Marra, Pandharipande, Girard, Ely, and Brummel designed and conducted the study. Drs. Thompson and Chandrasekhar contributed to statistical analysis. Drs. Marra and Brummel drafted the article. Drs. Pandharipande, Girard, Ely, and Brummel obtained funding. All authors contributed to data acquisition, analysis, and interpretation of the data; critical revision of the article for important intellectual content; and final approval of the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by the Department of Veterans Affairs Tennessee Valley Health Care System Geriatric Research, Education, and Clinical Center and VA-MERIT, the National Institutes of Health under awards (K76AG054864, R01AG027472, KL2TR000446, R03AG040549, R01AG035117, R01HL111111, R01GM120484) and the Doris Duke Foundation. Drs. Pandharipande, Girard, Patel, Hughes, Jackson, Ely, and Brummel received support for article research from the National Institutes of Health (NIH). Dr. Pandharipande received other support from a research grant from Hospira in collaboration with the NIH. Dr. Girard’s institution received funding from NIH AG034257 and NIH HL135144. Dr. Ely received honoraria from NIH and VA funding, and he received funding from Orion Pharma, Pfizer, and Abbott Laboratories for continuing medical education activities. Dr. Brummel received an honorarium from ArjoHuntleigh for advisory board activities. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: nathan.brummel@vanderbilt.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.