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

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

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

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

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

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

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

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

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

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

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

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

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

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

Timothy Barkham, Anna Sheppard, Nicola Jones, Swaine Chen

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

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

A. Heffernan, J. Lipman, J. Roberts

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

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

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

Brendon P. Scicluna

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

Sarah Masson-Roy

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 8, Page 985-986, April 15, 2018.

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.

Mathieu, Calypso; Desrois, Martine; Kober, Frank; Lalevée, Nathalie; Lan, Carole; Fourny, Natacha; Iché-Torres, Magali; Tran, Thi Thom; Lê, Linh Thuy; Singer, Mervyn; Mège, Jean-Louis; Bernard, Monique; Leone, Marc

Objectives: To investigate any gender effect of the beta-1 adrenergic blocker, landiolol, on cardiac performance and energy metabolism in septic rats, and to explore the expression of genes and proteins involved in this process. Design: Randomized animal study. Setting: University research laboratory. Subjects: Male and female Wistar rats. Interventions: One hour after cecal ligation and puncture, male and female rats were randomly allocated to the following groups: sham male, cecal ligation and puncture male, cecal ligation and puncture + landiolol male, sham female, cecal ligation and puncture female, and cecal ligation and puncture + landiolol female. Cardiac MRI was carried out 18 hours after cecal ligation and puncture to assess in vivo cardiac function. Ex vivo cardiac function measurement and 31P magnetic resonance spectroscopy were subsequently performed using an isovolumic isolated heart preparation. Finally, we assessed cardiac gene and protein expression. Measurements and Main Results: In males, landiolol increased indexed stroke volume by reversing the indexed end-diastolic volume reduction without affecting left ventricle ejection fraction. In females, landiolol did not increase indexed stroke volume and indexed end-diastolic volume but decreased left ventricle ejection fraction. Landiolol had no effect on ex vivo cardiac function and on high-energy phosphate compounds. The effect of landiolol on the gene expression of natriuretic peptide receptor 3 and on protein expression of phosphorylated-AKT:AKT ratio and endothelial nitric oxide synthase was different in males and females. Conclusions: Landiolol improved the in vivo cardiac performance of septic male rats while deleterious effects were reported in females. Expression of natriuretic peptide receptor 3, phosphorylated-AKT:AKT, and endothelial nitric oxide synthase are signaling pathways to investigate to better understand the sex differences 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 Fondation pour la Recherche Médicale (DEA 20150633224), AOP Orphan, Lions Club Marseille Doyen and France Life Imaging (grant ANR-11-INBS-0006). Dr. Mathieu received funding from Fondation Recherche Médicale (DEA20150633224) and Lions club Marseille Doyen. Dr. Singer received funding from AOP Pharma. Dr. Mege disclosed government work. Dr. Leone’s institution received funding from AOP Orphan (provided treatment: landiolol). The remaining authors do not have any potential conflicts of interest. For information regarding this article, Email: marc.leone@ap-hm.fr Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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

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

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.

Hampton T.

Previous research has shown platelets are involved in the innate immune response to pathogens via toll-like receptor expression, and evidence is emerging that they may also be important for adaptive immunity. A new study published in the Proceedings of the National Academy of Sciences has uncovered an unappreciated role of platelets in antibody-mediated adaptive immune responses.

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

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

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

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

Sweeney, Timothy E.; Azad, Tej D.; Donato, Michele; Haynes, Winston A.; Perumal, Thanneer M.; Henao, Ricardo; Bermejo-Martin, Jesús F.; Almansa, Raquel; Tamayo, Eduardo; Howrylak, Judith A.; Choi, Augustine; Parnell, Grant P.; Tang, Benjamin; Nichols, Marshall; Woods, Christopher W.; Ginsburg, Geoffrey S.; Kingsmore, Stephen F.; Omberg, Larsson; Mangravite, Lara M.; Wong, Hector R.; Tsalik, Ephraim L.; Langley, Raymond J.; Khatri, Purvesh

Objectives: To find and validate generalizable sepsis subtypes using data-driven clustering. Design: We used advanced informatics techniques to pool data from 14 bacterial sepsis transcriptomic datasets from eight different countries (n = 700). Setting: Retrospective analysis. Subjects: Persons admitted to the hospital with bacterial sepsis. Interventions: None. Measurements and Main Results: A unified clustering analysis across 14 discovery datasets revealed three subtypes, which, based on functional analysis, we termed “Inflammopathic, Adaptive, and Coagulopathic.” We then validated these subtypes in nine independent datasets from five different countries (n = 600). In both discovery and validation data, the Adaptive subtype is associated with a lower clinical severity and lower mortality rate, and the Coagulopathic subtype is associated with higher mortality and clinical coagulopathy. Further, these clusters are statistically associated with clusters derived by others in independent single sepsis cohorts. Conclusions: The three sepsis subtypes may represent a unifying framework for understanding the molecular heterogeneity of the sepsis syndrome. Further study could potentially enable a precision medicine approach of matching novel immunomodulatory therapies with septic patients most likely to benefit. Since the time the work was completed, Dr. Sweeney’s affiliation has changed to Inflammatix. The views expressed are those of the authors and do not reflect the official policy or position of the Department of Veterans Affairs, the Department of Defense, or the U.S. Government. Drs. Sweeney and Khatri contributed to study conception and design; Drs. Bermejo-Martin, Almansa, Tamayo, Howrylak, Choi, Parnell, Tang, Nichols, Woods, Ginsburg, Kingsmore, Wong, Tsalik, and Langley contributed materials; Drs. Sweeney, Azad, Donato, Haynes, Perumal, Henao, Omberg, Mangravite, Wong, and Khatri contributed methods; Dr. Sweeney performed the analyses; Dr. Sweeney drafted the article; all authors 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). Supported, in part, by Defense Advanced Research Projects Agency and the Army Research Office through Grant W911NF-15-1-0107. The CAPSOD study was supported, in part, by the National Institutes of Health grants U01AI066569, P20RR016480, HHSN266200400064C. The views expressed are those of the authors and do not reflect the official policy or position of the Department of Veterans Affairs, the Department of Defense, or the U.S. Government. Drs. Sweeney, Donato, Howrylak, Choi, Nichols, Kingsmore, Wong, Langley, and Khatri received support for article research from the National Institutes of Health (NIH). Drs. Bermejo-Martin, Almansa, Tamayo, and Khatri were supported by Instituto de Salud Carlos III (grants EMER07/050, PI13/02110, PI16/01156). Dr. Wong was supported by National Institute of General Medical Sciences grants R01GM099773 and R01GM108025. Drs. Sweeney, Nichols, and Khatri received support from the Bill & Melinda Gates Foundation. Drs. Sweeney and Khatri are cofounders of Inflammatix, which has a commercial interest in sepsis diagnostics, but played no role in this study. Drs. Donato’s and Wongs’ institutions received funding from the NIH. Drs. Perumal, Mangravite, and Langley received support for article research from Defense Advanced Research Projects Agency (DARPA). Dr. Henao received funding from OncocellMDx and InfiniaML. Dr. Nichols also received support for article research from the Defense Advanced Research Projects Agency Army Research Office. Dr. Howrylak also received support for article research from the National Center for Advancing Translational Sciences (UL1 TR000127 and KL2 TR000126). Dr. Ginsburg received other support as a founder of Host Response. Drs. Omberg’s and Mangravite’s institutions received funding from DARPA. Dr. Tsalik’s institution received funding from Novartis Vaccines and Diagnostics, and he disclosed other support (unrelated to this work) from grants from the NIH, DARPA, Defense Threat Reduction Agency, and the Henry M. Jackson Foundation; research support from bioMerieux and BioFire Diagnostics; consulting for Immunexpress, and bioMerieux; employment by Duke University and the Durham VA Health Care System; patents (or patents pending) for the Molecular Classification of Bacterial Infection, and Methods to Diagnose and Treat Acute Respiratory Infections; and equity in Host Response. Dr. Langley was supported by the National Center for Advancing Translational Sciences of the NIH under award number UL1TR001417. Dr. Khatri’s institution received funding from the NIH and the Bill & Melinda Gates Foundation and he received funding from Inflammatix and he is supported by grants from the National Institute for Allergy and Infectious Diseases (grants 1U19AI109662, U19AI057229 and U54I117925). The 33-gene set has been disclosed to the Stanford Office of Technology Licensing for possible patent protection. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: tes17@alumni.stanford.edu; pkhatri@stanford.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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

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

Røsjø, Helge; Masson, Serge; Caironi, Pietro; Stridsberg, Mats; Magnoli, Michela; Christensen, Geir; Moise, Gabriella; Urbano, Maria Cristina; Gattinoni, Luciano; Pesenti, Antonio; Latini, Roberto; Omland, Torbjørn; for the ALBIOS Biomarkers Study Investigators

Objectives: Secretoneurin directly influences cardiomyocyte calcium handling, and circulating secretoneurin levels seem to improve risk prediction in patients with myocardial dysfunction by integrating information on systemic stress, myocardial function, and renal function. Accordingly, in this study, we hypothesized that secretoneurin would improve risk prediction in patients with sepsis and especially in patients with septic shock as these patients are more hemodynamically unstable. Design: Multicenter, interventional randomized clinical trial. Setting: Multicenter, pragmatic, open-label, randomized, prospective clinical trial testing fluid administration with either 20% human albumin and crystalloids or crystalloid solutions alone in patients with severe sepsis or septic shock (The Albumin Italian Outcome Sepsis). Patients or Subjects: In total, 540 patients with septic shock and 418 patients with severe sepsis. Interventions: Either 20% human albumin and crystalloids or crystalloid solutions alone. Measurements and Main Results: We measured secretoneurin on days 1, 2, and 7 after randomization and compared the prognostic value of secretoneurin for ICU and 90-day mortality with established risk indices and cardiac biomarkers in septic shock and severe sepsis. High secretoneurin levels on day 1 were associated with age and serum concentrations of lactate, bilirubin, creatinine, and N-terminal pro-B-type natriuretic peptide. Adjusting for established risk factors and cardiovascular biomarkers, secretoneurin levels on day 1 were associated with ICU (odds ratio, 2.27 [95% CI, 1.05–4.93]; p = 0.04) and 90-day mortality (2.04 [1.02–4.10]; p = 0.04) in patients with septic shock, but not severe sepsis without shock. Secretoneurin levels on day 2 were also associated with ICU (3.11 [1.34–7.20]; p = 0.008) and 90-day mortality (2.69 [1.26–5.78]; p = 0.01) in multivariate regression analyses and improved reclassification in patients with septic shock, as assessed by the net reclassification index. Randomized albumin administration did not influence the associations between secretoneurin and outcomes. Conclusions: Secretoneurin provides early and potent prognostic information in septic patients with cardiovascular instability. 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). A complete list of centers and investigators participating in the Albumin Italian Outcome Sepsis substudy has been published elsewhere: Masson S, Caironi P, Spanuth E, et al; ALBIOS Study Investigators: Presepsin (soluble CD14 subtype) and procalcitonin levels for mortality prediction in sepsis: Data from the Albumin Italian Outcome Sepsis trial. Crit Care 2014; 18:R6. The Albumin Italian Outcome Sepsis trial was funded by a grant from the Agenzia Italiana del Farmaco (AIFA) (grant FARM6JS3R5, 2006). This project was also funded by Akershus University Hospital, the Research Council of Norway, the University of Oslo, and the South-Eastern Norway Regional Health Authority. Supported, in part, by funding from the Italian Ministry of Health (Ricerca Finalizzata, grant number RF-2011-02348358). Roche Diagnostics (Rotkreuz, Switzerland) provided in kind reagents for measuring N-terminal pro B-type natriuretic peptide and high-sensitive cardiac troponin T. Dr. Røsjø received personal fees from Novartis and CardiNor AS. Dr. Røsjø disclosed that this project was funded by Akershus University Hospital, the Research Council of Norway, the University of Oslo, and the South-Eastern Norway Regional Health Authority. Roche Diagnostics (Rotkreuz, Switzerland) provided in kind reagents for measuring N-terminal pro B-type natriuretic peptide and high sensitive cardiac troponin T. Dr. Røsjø has financial interests in CardiNor AS, which holds the license to commercialize secretoneurin. Drs. Masson’s and Caironi’s institutions received funding from the AIFA (grant FARM6JS3R5, 2006) and the Italian Ministry of Health (Ricerca Finalizzata, grant number RF-2011-02348358). Dr. Caironi received funding from Bbraun (lecture honoraria), Grifols (lecture honoraria and grant: Albumin Awards Program Grifols Award), and Ortho Diagnostic (lecture honoraria). Dr. Stridsberg received personal fees from CardiNor AS. Drs. Røsjø, Stridsberg, and Omland are partners in a patent filed by the University of Oslo regarding the use of secretoneurin as a biomarker in patients with cardiovascular disease and patients with critical illness. Dr. Christensen disclosed that he is a partner in a patent filed by the University of Oslo regarding the use of secretoneurin as a biomarker in patients with cardiovascular disease and patients with critical illness and has financial interests in CardiNor AS, which holds the license to commercialize secretoneurin. Dr. Urbano received support for article research from the National Institutes of Health and disclosed work for hire. Dr. Gattinoni received funding from Grifols (jury member for Albumin Grifols Award) and expert testimony in legal trials. Dr. Pesenti’s institution received funding from AIFA Official Italian agency for drug safety and studies, and he received funding from Xenios and Baxter. Dr. Omland’s institution received funding from Akershus University Hospital, Research Council of Norway, University of Oslo, and the South-Eastern Norway Regional Health Authority, and he received funding from Roche Diagnostics, Abbott Diagnostics, Bayer, Novartis, and CardiNor. The remaining authors have disclosed that they do not have any potential conflicts of interest. Address requests for reprints to: Helge Røsjø, MD, PhD, Division of Medicine, Akershus University Hospital, Sykehusveien 25, 1478 Lørenskog, Norway. E-mail: helge.rosjo@medisin.uio.no Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Chaudhary, Ninad S.; Donnelly, John P.; Wang, Henry E.

Objectives: To determine the racial disparities in severe sepsis hospitalizations and outcomes in U.S. academic medical center–affiliated hospitals. Design: Retrospective analysis of sepsis hospitalizations. Settings: U.S. academic medical center–affiliated hospitals participating in Vizient Consortium from 2012 to 2014. Patients: Sepsis hospitalizations using International Classification of Diseases, Ninth revision, discharge diagnoses codes defined by the Angus method. Interventions: None. Measurements and Main Results: We compared rates of sepsis hospitalization, ICU admission, organ dysfunction, and hospital mortality between blacks and whites. We repeated the analyses stratified by community-acquired, healthcare-associated, and hospital-acquired sepsis subtypes. Of 10,244,780 hospitalizations in our cohort, 1,114,386 (10.9%) had sepsis. Sepsis subtypes included community-acquired sepsis (61.8%), healthcare-associated sepsis (23.8%), and hospital-acquired sepsis (14.4%). Although the proportion of discharges with sepsis was lower for blacks than whites (106.72 vs 109.43 per 1,000 hospitalizations; p < 0.001), the proportion of black sepsis hospitalizations was higher for individuals greater than 30 years old. Blacks exhibited lower adjusted sepsis hospital mortality than whites (odds ratio, 0.85; 95% CI, 0.84–0.86). The adjusted odds of hospital mortality following community-acquired, healthcare-associated, and hospital-acquired sepsis were lower for blacks than whites. Conclusions: In this current series of hospital discharges at U.S. academic medical center–affiliated hospitals, blacks exhibited lower adjusted rates of sepsis hospitalizations and mortality than whites. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. All authors conceived the study. Dr. Wang obtained funding. Dr. Chaudhary and Mr. Donnelly conducted the analysis. Dr. Chaudhary drafted the article, and all authors contributed to its critical review. Dr. Wang assumes overall responsibility for 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). Mr. Donnelly was supported by the National Institute of General Medical Sciences (F31-GM122180) of the National Institutes of Health (NIH). Mr. Donnelly’s institution received funding from the NIH/National Institute of General Medical Sciences, and he received support for article research from the NIH. Dr. Wang was supported by the National Institute of Nursing Research (R01-NR012726). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: hwang@uabmc.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Ryoo, Seung Mok; Lee, JungBok; Lee, Yoon-Seon; Lee, Jae Ho; Lim, Kyoung Soo; Huh, Jin Won; Hong, Sang-Bum; Lim, Chae-Man; Koh, Younsuck; Kim, Won Young

Objectives: This study aimed to compare the prognostic value of lactate level and lactate clearance at 6 hours after septic shock recognition. And, we performed it to determine lactate kinetics in the Sepsis-3 defined septic shock. Design: This retrospective study was performed from a prospective septic shock registry. Settings: This study was performed at single urban tertiary center. And, all patients were treated with protocol-driven resuscitation bundle therapy between 2010 and 2016. Patients: We included septic shock patients who met the Sepsis-3 definition, which involves lactate levels greater than or equal to 2 mmol/L and vasopressor use. Interventions: Serum lactate levels were measured at initial and 6 hours from septic shock recognition. Measurements and Main Results: Lactate clearance was calculated as ([initial lactate – 6-hr lactate]/initial lactate) × 100. The prognostic value of measured lactate levels and lactate clearance for 28-day mortality was analyzed and compared with that of subsequent lactate levels greater than or equal to 2 mmol/L, greater than or equal to 3 mmol/L, and greater than or equal to 4 mmol/L and less than 10%, less than 20%, and less than 30% lactate clearance. A total of 1,060 septic shock patients by Sepsis-3, 265 patients died (28-d mortality: 25%). In survivor, groups had lower median 6-hour lactate level and higher lactate clearance than nonsurvivors (2.5 vs 4.6 mmol/L and 35.4% vs 14.8%; p < 0.01). Both lactate and lactate clearance were associated with mortality after adjusting for confounders (odd ratio, 1.27 [95% CI, 1.21–1.34] and 0.992 [95% CI, 0.989–0.995]), but lactate had a significantly higher prognostic value than lactate clearance (area under the curve, 0.70 vs 0.65; p < 0.01). The prognostic value of subsequent lactate levels (≥ 2, ≥ 3, and ≥ 4 mmol/L) and lactate clearances (< 10%, < 20%, and < 30%) was not significantly differed. However, lactate levels of greater than or equal to 2 mmol/L had the greatest sensitivity (85.3%). Conclusions: Our findings indicate lactate and lactate clearance are both useful targets in patients with septic shock defined by Sepsis-3. Serum lactate level at 6-hour can be an easier and more effective tool for prognosis of septic shock patients who were treated with protocol-driven resuscitation bundle therapy. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by a grant (2017-0116) from the Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea. The authors have disclosed that they do not have any potential conflicts of interest. Address requests for reprints to: Won Young Kim, MD, PhD, Department of Emergency Medicine, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea. E-mail: wonpia73@naver.com Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Schuler, Alejandro; Wulf, David A.; Lu, Yun; Iwashyna, Theodore J.; Escobar, Gabriel J.; Shah, Nigam H.; Liu, Vincent X.

Objectives: To estimate the impact of each of six types of acute organ dysfunction (hepatic, renal, coagulation, neurologic, cardiac, and respiratory) on long-term mortality after surviving sepsis hospitalization. Design: Multicenter, retrospective study. Settings: Twenty-one hospitals within an integrated healthcare delivery system in Northern California. Patients: Thirty thousand one hundred sixty-three sepsis patients admitted through the emergency department between 2010 and 2013, with mortality follow-up through April 2015. Interventions: None. Measurements and Main Results: Acute organ dysfunction was quantified using modified Sequential Organ Failure Assessment scores. The main outcome was long-term mortality among sepsis patients who survived hospitalization. The estimates of the impact of each type of acute organ dysfunction on long-term mortality were based on adjusted Cox proportional hazards models. Sensitivity analyses were conducted based on propensity score–matching and adjusted logistic regression. Hospital mortality was 9.4% and mortality was 31.7% at 1 year. Median follow-up time among sepsis survivors was 797 days (interquartile range: 384–1,219 d). Acute neurologic (odds ratio, 1.86; p < 0.001), respiratory (odds ratio, 1.43; p < 0.001), and cardiac (odds ratio, 1.31; p < 0.001) dysfunction were most strongly associated with short-term hospital mortality, compared with sepsis patients without these organ dysfunctions. Evaluating only patients surviving their sepsis hospitalization, acute neurologic dysfunction was also most strongly associated with long-term mortality (odds ratio, 1.52; p < 0.001) corresponding to a marginal increase in predicted 1-year mortality of 6.0% for the presence of any neurologic dysfunction (p < 0.001). Liver dysfunction was also associated with long-term mortality in all models, whereas the association for other organ dysfunction subtypes was inconsistent between models. Conclusions: Acute sepsis-related neurologic dysfunction was the organ dysfunction most strongly associated with short- and long-term mortality and represents a key mediator of long-term adverse outcomes following sepsis. This work does not necessarily represent the views of the U.S. Government or Department of Veterans Affairs. 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 Permanente Medical Group. Dr. Liu was supported by the National Institutes of Health K23GM112018; Dr. Iwashyna was supported by VA HSR&D IIR 13–079. Dr. Schuler disclosed work for hire. Dr. Iwashyna disclosed government work. Dr. Escobar’s institution received funding from National Institute of General Medical Sciences. Drs. Escobar, Shah, and Liu 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: Vincent.x.liu@kp.org Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.