Sepsis

by Ryo Ueno, Takateru Masubuchi, Atsushi Shiraishi, Satoshi Gando, Toshikazu Abe, Shigeki Kushimoto, Toshihiko Mayumi, Seitaro Fujishima, Akiyoshi Hagiwara, Toru Hifumi, Akira Endo, Takayuki Komatsu, Joji Kotani, Kohji Okamoto, Junichi Sasaki, Yasukazu Shiino, Yutaka Umemura This study aimed to assess the value of quick sequential organ failure assessment (qSOFA) combined with other risk factors in predicting in-hospital mortality in patients presenting to the emergency department with suspected infection. This post-hoc analysis of a prospective multicenter study dataset included 34 emergency departments across Japan (December 2017 to February 2018). We included adult patients (age ≥16 years) who presented to the emergency department with suspected infection. qSOFA was calculated and recorded by senior emergency physicians when they suspected an infection. Different types of sepsis-related risk factors (demographic, functional, and laboratory values) were chosen from prior studies. A logistic regression model was used to assess the predictive value of qSOFA for in-hospital mortality in models based on the following combination of predictors: 1) qSOFA-Only; 2) qSOFA+Age; 3) qSOFA+Clinical Frailty Scale (CFS); 4) qSOFA+Charlson Comorbidity Index (CCI); 5) qSOFA+lactate levels; 6) qSOFA+Age+CCI+CFS+lactate levels. We calculated the area under the receiver operating characteristic curve (AUC) and other key clinical statistics at Youden’s index, where the sum of sensitivity and specificity is maximized. Following prior literature, an AUC >0.9 was deemed to indicate high accuracy; 0.7–0.9, moderate accuracy; 0.5–0.7, low accuracy; and 0.5, a chance result. Of the 951 patients included in the analysis, 151 (15.9%) died during hospitalization. The AUC for predicting in-hospital mortality was 0.627 (95% confidence interval [CI]: 0.580−0.673) for the qSOFA-Only model. Addition of other variables only marginally improved the model’s AUC; the model that included all potentially relevant variables yielded an AUC of only 0.730 (95% CI: 0.687–0.774). Other key statistic values were similar among all models, with sensitivity and specificity of 0.55−0.65 and 0.60−0.75, respectively. In this post-hoc data analysis from a prospective multicenter study based in Japan, combining qSOFA with other sepsis-related risk factors only marginally improved the model’s predictive value.

Objectives: To determine whether race is a major determinant of sepsis outcomes when controlling for socioeconomic factors. Design: Retrospective cohort study. Setting: Barnes-Jewish Hospital a 1,350 bed academic medical center. Patients: Eleven-thousand four-hundred thirty-two patients hospitalized between January 2010 and April 2017 with sepsis and septic shock. Interventions: Multilevel random effects modeling was employed whereby patients were nested within ZIP codes. Individual patient characteristics and socioeconomic variables aggregated at the ZIP code level (education, employment status, income, poverty level, access to healthcare) were included in the model. Measurements and Main Results: In hospital mortality, length of stay, need for vasopressors, and mechanical ventilation were the main endpoints. Black patients had more comorbidities than White patients except for cirrhosis and malignancy. In unadjusted comparisons, White individuals were more likely to require mechanical ventilation and had higher mortality rates and longer hospital stays for both low- and high-income groups. When nesting within ZIP codes and accounting for socioeconomic variables, race did not have a significant effect on mortality. Non-White races had lower odds ratio for mechanical ventilation. Conclusions: Our study demonstrates that race is not an independent risk factor for sepsis mortality, as well as sepsis-related length of stay. We should expand our inquiry into determinants of sepsis outcomes by including socioeconomic variables. This work was performed at Barnes-Jewish Hospital. 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. Vazquez Guillamet’s institution received funding from the National Institute of General Medical Sciences of the National Institutes of Health (NIH) award K08 GM140310-01. Drs. Vazquez Guillamet and Kollef received support for article research from the NIH. Dr. Dodda received funding from St. Louis College of Pharmacy from the Women’s Giving Initiative Grant. Dr. Liu’s institution received funding from Washington University from an internal grant; he received funding from Mesoblast and Adial. Dr. Kollef received funding from the Barnes-Jewish Hospital Foundation. Dr. Micek received funding from Shionogi. For information regarding this article, E-mail: kollefm@wustl.edu Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objective: Coronavirus disease 2019 is a heterogeneous disease most frequently causing respiratory tract infection, which can induce respiratory failure and multiple organ dysfunction syndrome in its severe forms. The prevalence of coronavirus disease 2019–related sepsis is still unclear; we aimed to describe this in a systematic review. Data Sources: MEDLINE (PubMed), Cochrane, and Google Scholar databases were searched based on a prespecified protocol (International Prospective Register for Systematic Reviews: CRD42020202018). Study Selection: Studies reporting on patients with confirmed coronavirus disease 2019 diagnosed with sepsis according to sepsis-3 or according to the presence of infection-related organ dysfunctions necessitating organ support/replacement were included in the analysis. The primary end point was prevalence of coronavirus disease 2019–related sepsis among adults hospitalized in the ICU and the general ward. Among secondary end points were the need for ICU admission among patients initially hospitalized in the general ward and the prevalence of new onset of organ dysfunction in the ICU. Outcomes were expressed as proportions with respective 95% CI. Data Extraction: Two reviewers independently screened and reviewed existing literature and assessed study quality with the Newcastle-Ottawa Scale and the Methodological index for nonrandomized studies. Data Synthesis: Of 3,825 articles, 151 were analyzed, only five of which directly reported sepsis prevalence. Noting the high heterogeneity observed, coronavirus disease 2019–related sepsis prevalence was 77.9% (95% CI, 75.9–79.8; I2 = 91%; 57 studies) in the ICU, and 33.3% (95% CI, 30.3–36.4; I2 = 99%; 86 studies) in the general ward. ICU admission was required for 17.7% (95% CI, 12.9–23.6; I2 = 100%) of ward patients. Acute respiratory distress syndrome was the most common organ dysfunction in the ICU (87.5%; 95% CI, 83.3–90.7; I2 = 98%). Conclusions: The majority of coronavirus disease 2019 patients hospitalized in the ICU meet Sepsis-3 criteria and present infection-associated organ dysfunction. The medical and scientific community should be aware and systematically report viral sepsis for prognostic and treatment implications. 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. Reinhart and Kyriazopoulou contributed equally. Dr. Kyriazopoulou performed literature search and study selection, participated in data analysis, and drafted the article. Dr. Karakike performed literature search and study selection and participated in data analysis and drafting of the article. Dr. Kyprianou performed data analysis. Drs. Fleischmann-Struzek, Netea, and Reinhart conceptualized the study and revised the article for important intellectual content. Dr. Pletz revised the article for important intellectual content. Dr. Giamarellos-Bourboulis conceptualized the study and participated in literature search, study selection, and drafting the article. All authors gave approval for the version to be published. Dr. Karakike received funding from the Horizon 2020 Marie Skłodowska-Curie Grant European Sepsis Academy (grant 676129). Dr. Netea’s institution received funding from Roche; he received funding form an ERC Advanced Grant (833247), a Spinoza grant of the Netherlands Organization for Scientific Research, TTxD, GSK, and ViiV HealthCare; he disclosed he is on the scientific Advisory Board at Trained Therapeutic and Discovery; received independent educational grants from AbbVie, Abbott CH, Astellas Pharma Europe, AxisShield, bioMérieux, InflaRx GmbH, the Medicines Company, and XBiotech. Dr. Reinhart disclosed that he was the President of the Global Sepsis Alliance and that he is a shareholder of InflaRx NV, a Jena/Germany-based Biotech Company that evaluates an immune-modulatory approach for the adjunctive treatment of coronavirus disease 2019. Dr. Giamarellos-Bourboulis’ institution received funding from the Framework 7 Program, HemoSpec (granted to the National and Kapodistrian University of Athens), the Horizon 2020 Marie-Curie Project European Sepsis Academy (granted to the National and Kapodistrian University of Athens), and the Horizon 2020 European Grant ImmunoSep (granted to the Hellenic Institute for the Study of Sepsis); he received funding from AbbVie, United States; Abbott CH; Angelini; Astellas Pharma; AxisShield; bioMérieux; Biotest; Brahms GmbH; InflaRx GmbH; MSD Greece; XBiotech; and The Medicines Company; independent educational grants from AbbVie, Abbott CH, Astellas Pharma Europe, AxisShield, bioMérieux, InflaRx GmbH, the Medicines Company, and XBiotech. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: egiamarel@med.uoa.gr Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

No abstract available…

Objectives No validated, simple, powerful and continuously monitorable risk prediction tools are available for patients with sepsis during the early phases in the emergency department (ED). We sought to derive a novel Simple Sepsis Early Prognostic Score (SSEPS) composed of physiological indicators that do not depend on laboratory tests and that can be used by emergency clinicians in predicting outcomes in patients with sepsis. Design Retrospective cohort analysis of a collected data source. Participants Patients with sepsis admitted to the ED of the West China Hospital of Sichuan University between July 2015 and June 2016 were included. We excluded patients who were pregnant, those with cardiac or respiratory arrest, and those using vasoactive drugs before admission to the ED. Primary outcome measures 28-day all-cause mortality. Results The SSEPS consisted of age, heart rate, respiratory rate and altered consciousness. Patients in the development cohort with higher SSEPS had a significantly higher mortality (first tertile vs second tertile vs third tertile: 12.5% vs 28.6% vs 53.5%, p<0.001). The area under the receiver operating characteristic curve for SSEPS was 0.762 (95% CI 0.686 to 0.838), which was similar to Sequential Organ Failure Assessment (SOFA) (area under the curve: 0.745, 95% CI 0.692 to 0.798) and Acute Physiology and Chronic Health Evaluation (APACHE II) (area under the curve: 0.750, 95% CI 0.681 to 0.819). Moreover, the decision curve analysis showed that the net benefit of SSEPS was higher than SOFA and APACHE II at any probability threshold. Conclusion The SSEPS is simple and useful for clinicians in stratifying high-risk patients with sepsis at the early phase of ED admission.

Objectives: To train a model to predict vasopressor use in ICU patients with sepsis and optimize external performance across hospital systems using domain adaptation, a transfer learning approach. Design: Observational cohort study. Setting: Two academic medical centers from January 2014 to June 2017. Patients: Data were analyzed from 14,512 patients (9,423 at the development site and 5,089 at the validation site) who were admitted to an ICU and met Center for Medicare and Medicaid Services definition of severe sepsis either before or during the ICU stay. Patients were excluded if they never developed sepsis, if the ICU length of stay was less than 8 hours or more than 20 days or if they developed shock up to the first 4 hours of ICU admission. Measurements and Main Results: Forty retrospectively collected features from the electronic medical records of adult ICU patients at the development site (four hospitals) were used as inputs for a neural network Weibull-Cox survival model to derive a prediction tool for future need of vasopressors. Domain adaptation updated parameters to optimize model performance in the validation site (two hospitals), a different healthcare system over 2,000 miles away. The cohorts at both sites were randomly split into training and testing sets (80% and 20%, respectively). When applied to the test set in the development site, the model predicted vasopressor use 4–24 hours in advance with an area under the receiver operator characteristic curve, specificity, and positive predictive value ranging from 0.80 to 0.81, 56.2% to 61.8%, and 5.6% to 12.1%, respectively. Domain adaptation improved performance of the model to predict vasopressor use within 4 hours at the validation site (area under the receiver operator characteristic curve 0.81 [CI, 0.80–0.81] from 0.77 [CI, 0.76–0.77], p < 0.01; specificity 59.7% [CI, 58.9–62.5%] from 49.9% [CI, 49.5–50.7%], p < 0.01; positive predictive value 8.9% [CI, 8.5–9.4%] from 7.3 [7.1–7.4%], p < 0.01). Conclusions: Domain adaptation improved performance of a model predicting sepsis-associated vasopressor use during external validation. 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. Holder conceptualized and contributed to the study design and data interpretation, and drafted the article. Dr. Nemati contributed to the study design, acquired the data, and led the analysis, and contributed to data interpretation and draft revision with critical intellectual content. Dr. Wardi contributed to the data interpretation and to draft revision with intellectual content. Dr. Shashikumar contributed to the study design, analysis, and draft revision. Dr. Buchman contributed to data interpretation and draft revision with intellectual content. All authors gave final approval of the article submitted for publication and agreed to be accountable for all aspects of the work. Dr. Holder is supported by the National Institute of General Medical Sciences of the National Institutes of Health (K23GM37182). Dr. Nemati is funded by the National Institutes of Health (#K01ES025445) and the Gordon and Betty Moore Foundation (#GBMF9052). Dr. Wardi is supported by the National Foundation of Emergency Medicine and funding from the Gordon and Betty Moore Foundation (#GBMF9052). He has received speakers’ fees from Thermo-Fisher and consulting fees from General Electric. Dr. Buchman’s institution received funding from the Henry M. Jackson Foundation for his role as site director in Surgical Critical Care Institute, http://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) and from Society of Critical Care Medicine for his role as Editor-in-Chief of Critical Care Medicine. Dr. Buchman is jointly hired under the Intergovernmental Personnel Act Mobility Program by Emory University and the Biomedical Advanced Research and Development Authority, which is under the United States Department of Health and Human Services. Funders played no role in study design, collection of data, analysis, reporting, or interpretation of results. Dr. Shashikumar has disclosed that he does not have any potential conflicts of interest. For information regarding this article, E-mail: andre.holder@emory.edu Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: To describe the epidemiology of sepsis in critical care by applying the Sepsis-3 criteria to electronic health records. Design: Retrospective cohort study using electronic health records. Setting: Ten ICUs from four U.K. National Health Service hospital trusts contributing to the National Institute for Health Research Critical Care Health Informatics Collaborative. Patients: A total of 28,456 critical care admissions (14,332 emergency medical, 4,585 emergency surgical, and 9,539 elective surgical). Measurements and Main Results: Twenty-nine thousand three hundred forty-three episodes of clinical deterioration were identified with a rise in Sequential Organ Failure Assessment score of at least 2 points, of which 14,869 (50.7%) were associated with antibiotic escalation and thereby met the Sepsis-3 criteria for sepsis. A total of 4,100 episodes of sepsis (27.6%) were associated with vasopressor use and lactate greater than 2.0 mmol/L, and therefore met the Sepsis-3 criteria for septic shock. ICU mortality by source of sepsis was highest for ICU-acquired sepsis (23.7%; 95% CI, 21.9–25.6%), followed by hospital-acquired sepsis (18.6%; 95% CI, 17.5–19.9%), and community-acquired sepsis (12.9%; 95% CI, 12.1–13.6%) (p for comparison less than 0.0001). Conclusions: We successfully operationalized the Sepsis-3 criteria to an electronic health record dataset to describe the characteristics of critical care patients with sepsis. This may facilitate sepsis research using electronic health record data at scale without relying on human coding. 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. Shah and MacCallum are the joint first authors. Drs. Shah and Harris analyzed the data. Drs. MacCallum, Harris, Brealey, Hetherington, Shi, Perez-Suarez developed the database platform and research methods. Drs. Shah, MacCallum, and Singer drafted the article. All authors contributed to intellectual content to the article. Dr. Singer supervised the study. This work was supported, in part, by the Biomedical Research Centres based at the University College Hospitals (UCLH) National Health Service (NHS) Foundation Trust and University College London (UCL), Imperial College Healthcare NHS Trust and Imperial College London, Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge, Oxford University Hospitals NHS Foundation Trust and the University of Oxford, and Guy’s and St. Thomas’ NHS Foundation Trust and King’s College London. This research was also supported by the UCL/UCLH Clinical Research Informatics Unit and conducted using National Institute for Health Research Health Informatics Collaborative data resources. This work uses data provided by patients and collected by the National Health Service as part of their care and support. Drs. Shah’s, Watkinson’s, and Brett’s institutions received funding from the National Institute for Health Research (NIHR). Dr. Shah is supported by a postdoctoral fellowship funded by the Health Foundation's grant to the University of Cambridge for The Healthcare Improvement Studies Institute. Dr. Palmer received funding from the Medical Research Council and The London Clinic. Dr. Hetherington’s institution received funding from the United Kingdom Government; he received funding from Turing Institute and the Department of Health and Social Care; he received support for article research from Research Councils UK; he disclosed work for hire. Dr. Shi disclosed work for hire. Dr. Watkinson’s institution received funding from Wellcome and Sesnyne Health; he disclosed that he was the Chief Medical Officer for Sesnyne Health. Dr. Ashworth disclosed that he is an employee of Imperial College Healthcare National Health Service (NHS) Trust and the Clinical Director of Critical Care. Dr. Beale’s institution received funding from the Philips Medical Systems Medical Advisory Board; he disclosed that he is on the Steering Committee of the Surviving Sepsis Campaign. Dr. Singer’s institution received funding from Roche, Deltex, NewB, GE Healthcare, Pfizer, and Biomerieux. The views expressed are those of the authors and are not necessarily those of the NIHR, the NHS, or the United Kingdom Department of Health and Social Care. The remaining authors have disclosed that they do not have any potential conflicts of interest For information regarding this article, E-mail: a.shah@ucl.ac.uk This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: Widespread use and misuse of prescription and illicit opioids have exposed millions to health risks including serious infectious complications. Little is known, however, about the association between opioid use and sepsis. Design: Retrospective cohort study. Setting: About 373 U.S. hospitals. Patients: Adults hospitalized between January 2009 and September 2015. Interventions: None. MEASUREMENTS AND MAIN RESULTS: Sepsis was identified by clinical indicators of concurrent infection and organ dysfunction. Opioid-related hospitalizations were identified by the International Classification of Diseases, 9th Revision, Clinical Modification codes and/or inpatient orders for buprenorphine. Clinical characteristics and outcomes were compared by sepsis and opioid-related hospitalization status. The association between opioid-related hospitalization and all-cause, in-hospital mortality in patients with sepsis was assessed using mixed-effects logistic models to adjust for baseline characteristics and severity of illness. The cohort included 6,715,286 hospitalizations; 375,479 (5.6%) had sepsis, 130,399 (1.9%) had opioid-related hospitalizations, and 8,764 (0.1%) had both. Compared with sepsis patients without opioid-related hospitalizations (n = 366,715), sepsis patients with opioid-related hospitalizations (n = 8,764) were younger (mean 52.3 vs 66.9 yr) and healthier (mean Elixhauser score 5.4 vs 10.5), had more bloodstream infections from Gram-positive and fungal pathogens (68.9% vs 47.0% and 10.6% vs 6.4%, respectively), and had lower in-hospital mortality rates (10.6% vs 16.2%; adjusted odds ratio, 0.73; 95% CI, 0.60–0.79; p < 0.001 for all comparisons). Of 1,803 patients with opioid-related hospitalizations who died in-hospital, 928 (51.5%) had sepsis. Opioid-related hospitalizations accounted for 1.5% of all sepsis-associated deaths, including 5.7% of sepsis deaths among patients less than 50 years old. From 2009 to 2015, the proportion of sepsis hospitalizations that were opioid-related increased by 77% (95% CI, 40.7–123.5%). Conclusions: Sepsis is an important cause of morbidity and mortality in patients with opioid-related hospitalizations, and opioid-related hospitalizations contribute disproportionately to sepsis-associated deaths among younger patients. In addition to ongoing efforts to combat the opioid crisis, public health agencies should focus on raising awareness about sepsis among patients who use opioids and their providers. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). This work was funded by the Centers for Disease Control and Prevention (U54CK000484), the Agency for Healthcare Research and Quality (K08HS025008 to Dr. Rhee), and intramural funds from the National Institutes of Health Clinical Center and National Institute of Allergy and Infectious Diseases (to Dr. Kadri). Drs. Alrawashdeh’s, Klompas’s, Larochelle’s, and Rhee’s institutions received funding from the Centers for Disease Control and Prevention (CDC; U54CK000484). Drs. Alrawashdeh’s, Klompas, and Rhee’s institutions received funding from the Agency for Healthcare Research and Quality (AHRQ; K08HS025008). Drs. Alrawashdeh’s and Larochelle’s institutions received funding from the National Institutes of Health (NIH). Drs. Alrawashdeh, Kimmel, and Kadri received support for article research from the NIH. Dr. Klompas’ institution received funding from the Massachusetts Department of Public Health. Drs. Klompas and Rhee received funding from UpToDate. Dr. Kimmel received funding from Abt Associates on a Department of Public Health–funded project. Dr. Larochelle’s institution received funding from the National Institute on Drug Abuse and the Robert Wood Johnson Foundation; he received funding from the University of Baltimore, the Office of National Drug Control Policy, and OptumLabs. Drs. Gokhale, Hoots, Hatfield, Reddy, and Fiore received support for article research from the government. Drs. Reddy and Rhee received support for article research from the CDC. Dr. Rhee received support for article research from the AHRQ. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: mohammad_alrawashdeh@hms.harvard.edu Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Abstract Background Klebsiella pneumoniae is a primary pathogen of pyogenic liver abscess (PLA). However, little data are available on combination with sepsis. In this study, we aimed to evaluate the clinical characteristics and prognostic differences of PLA patients with sepsis. Methods This retrospective cohort study was conducted to investigate 135 patients with confirmed Klebsiella pneumoniae-caused liver abscesses (KPLA) from a tertiary teaching hospital, from 2013 to 2019. The patients were divided into two groups, KPLA with sepsis and KPLA without sepsis. The demographic characteristics, clinical features as well as laboratory and microbiologic findings were analyzed. Results A total of 135 patients with KPLA were analyzed. The mean age of patients was 60.9 ± 12.7 years, and the percentage of men was 59.3%. Among them, 37/135 (27.4%) of patients had sepsis and the mortality rate was 1.5%. The most common symptom was fever (91.1%). KPLA patients with sepsis had a significantly higher proportion of frailty, diarrhea, fatty liver, chronic renal insufficiency, and hepatic dysfunction compared to KPLA patients without sepsis (p < 0.05). Antibiotic therapy and percutaneous drainage were most frequently therapeutic strategy. Furthermore, the incidences of sepsis shock and acute respiratory distress syndrome were higher in the sepsis group compared to the non-sepsis group. As for metastatic infections, the lung was the most common site. In addition, KPLA patients with sepsis showed respiratory symptoms in 11 patients, endophthalmitis in 4 patients, and meningitis in 1 patient. Conclusion Our findings emphasize that KPLA patients combined with or without sepsis have different clinical features, but KPLA patients with sepsis have higher rates of complications and metastatic infections. Taken together, further surveillance and control of septic spread is essential for KPLA patients.

Objective To compare the daily practice of two emergency departments (ED) in the Netherlands, where systemic inflammatory response syndrome (SIRS) criteria and quick Sequential Organ Failure Assessment (qSOFA) score are used differently as screening tools for culture-positive sepsis. Design A prospective cross-sectional multicentre study. Setting Two EDs at two European clinical teaching hospitals in the Netherlands. Participants 760 patients with suspected infection who met SIRS criteria or had a qualifying qSOFA score who were treated at two EDs in the Netherlands from 1 January to 1 March 2018 were included. Methods SIRS criteria and qSOFA score were calculated for each patient. The first hospital treated the patients who met SIRS criteria following the worldwide Surviving Sepsis Campaign protocol. At the second hospital, only patients who met the qualifying qSOFA score received this treatment. Therefore, patients could be divided into five groups: (1) SIRS+, qSOFA–, not treated according to protocol (reference group); (2) SIRS+, qSOFA–, treated according to protocol; (3) SIRS+, qSOFA+, treated according to protocol; (4) SIRS–, qSOFA+, not treated according to protocol; (5) SIRS–, qSOFA+, treated according to protocol. Primary and secondary outcome measures To prove culture-positive sepsis was present, cultures were used as the primary outcome. Secondary outcomes were in-hospital mortality and intensive care unit (ICU) admission. Results 98.9% met SIRS criteria and 11.7% met qSOFA score. Positive predictive values of SIRS criteria and qSOFA score were 41.2% (95% CI 37.4% to 45.2%) and 48.1% (95% CI 37.4% to 58.9%), respectively. HRs were 0.79 (95% CI 0.40 to 1.56, p=0.500), 3.42 (95% CI 1.82 to 6.44, p<0.001), 18.94 (95% CI 2.48 to 144.89, p=0.005) and 4.97 (95% CI 1.44 to 17.16, p=0.011) for groups 2–5, respectively. Conclusion qSOFA score performed as well as SIRS criteria for identifying culture-positive sepsis and performed significantly better for predicting in-hospital mortality and ICU admission. This study shows that SIRS criteria are no longer necessary and recommends qSOFA score as the standard for identifying culture-positive sepsis in the ED. Trial registration number NL8315.

Abstract Background Sepsis is an overwhelming and life-threatening response to bacteria in bloodstream and a major cause of neonatal morbidity and mortality. Understanding the etiology and potential risk factors for neonatal sepsis is urgently required, particularly in low-income countries where burden of infection is high and its epidemiology is poorly understood. Methods A prospective observational cohort study was conducted between April 2016 and October 2017 in a level three NICU at a tertiary care hospital in Nepal to determine the bacterial etiology and potential risk factors for neonatal sepsis. Results Among 142 NICU admitted neonates, 15% (21/142) and 32% (46/142) developed blood culture-positive and -negative neonatal sepsis respectively. Klebsiella pneumoniae (34%, 15/44) and Enterobacter spp. (25%, 11/44) were the most common isolates. The antimicrobial resistance of isolates to ampicillin (100%, 43/43), cefotaxime (74%, 31/42) and ampicillin-sulbactam (55%, 21/38) were the highest. BlaTEM (53%, 18/34) and blaKPC (46%, 13/28) were the commonest ESBL and carbapenemase genes respectively. In univariate logistic regression, the odds of sepsis increased with each additional day of use of invasive procedures such as mechanical ventilation (OR 1.086, 95% CI 1.008–1.170), umbilical artery catheter (OR 1.375, 95% CI 1.049–1.803), intravenous cannula (OR 1.140, 95% CI 1.062–1.225); blood transfusion events (OR 3.084, 95% CI 1.407–6.760); NICU stay (OR 1.109, 95% CI 1.040–1.182) and failure to breast feed (OR 1.130, 95% CI 1.060–1.205). Sepsis odds also increased with leukopenia (OR 1.790, 95% CI 1.04–3.082), increase in C-reactive protein (OR 1.028, 95% CI 1.016–1.040) and decrease in platelets count (OR 0.992, 95% CI 0.989–0.994). In multivariate analysis, increase in IV cannula insertion days (OR 1.147, 95% CI 1.039–1.267) and CRP level (OR 1.028, 95% CI 1.008–1.049) increased the odds of sepsis. Conclusions Our study indicated various nosocomial risk factors and underscored the need to improve local infection control measures so as to reduce the existing burden of sepsis. We have highlighted certain sepsis associated laboratory parameters along with identification of antimicrobial resistance genes, which can guide for early and better therapeutic management of sepsis. These findings could be extrapolated to other low-income settings within the region.

Objectives: Although clinical presentation of coronavirus disease 2019 has been extensively described, immune response to severe acute respiratory syndrome coronavirus 2 remains yet not fully understood. Similarities with bacterial sepsis were observed; however, few studies specifically addressed differences of immune response between both conditions. Here, we report a longitudinal analysis of the immune response in coronavirus disease 2019 patients, its correlation with outcome, and comparison between severe coronavirus disease 2019 patients and septic patients. Design: Longitudinal, retrospective observational study. Setting: Tertiary-care hospital during the first 2020 coronavirus disease 2019 outbreak in France. Patients: All successive patients with confirmed severe acute respiratory syndrome coronavirus 2 infection admitted to the emergency department, medical ward, and ICU with at least one available immunophenotyping performed during hospital stay. Measurements and Main Results: Between March and April 2020, 247 patients with coronavirus disease 2019 were included and compared with a historical cohort of 108 severe septic patients. Nonsevere coronavirus disease 2019 patients (n = 153) presented normal or slightly altered immune profiles. Severe coronavirus disease 2019 (n = 94) immune profile differed from sepsis. Coronavirus disease 2019 exhibited profound and prolonged lymphopenia (mostly on CD3, CD4, CD8, and NK cells), neutrophilia, and human leukocyte antigen D receptor expression on CD14+ monocytes down-regulation. Surprisingly, coronavirus disease 2019 patients presented a unique profile of B cells expansion, basophilia, and eosinophilia. Lymphopenia, human leukocyte antigen D receptor expression on CD14+ monocytes down-regulation, and neutrophilia were associated with a worsened outcome, whereas basophilia and eosinophilia were associated with survival. Circulating immune cell kinetics differed between severe coronavirus disease 2019 and sepsis, lack of correction of immune alterations in coronavirus disease 2019 patients during the first 2 weeks of ICU admission was associated with death and nosocomial infections. Conclusions: Circulating immune cells profile differs between mild and severe coronavirus disease 2019 patients. Severe coronavirus disease 2019 is associated with a unique immune profile as compared with sepsis. Several immune features are associated with outcome. Thus, immune monitoring of coronavirus disease 2019 might be of help for patient management. Drs. Mansouri, Brumpt, Megarbane, and Mebazaa contributed equally. Dr. Roquetaillade designed the study, collected data, and wrote the article. Drs. Mansouri, Brumpt, Neuwirth, Le Dorze, Fontaine, Barthrze, Gayat, and Megarbane collected data, images and wrote the article. Drs. Gayat, Mebazaa, and Chousterman designed the study and wrote the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: charles.de-roquetaillade@aphp.fr Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: Evaluating whether there is a clinical benefit of using extracorporeal cytokine adsorption therapy in two indications. Design: Systematic review. Setting: Search on four databases, Medline, Embase, The Cochrane Library, and the European Network for Health Technology Assessment planned and ongoing projects database. PATIENTS: Patients with sepsis/septic shock; patients undergoing cardiac surgery INTERVENTIONS: Cytokine adsorption. Measurements and Main Results: Randomized controlled trials and prospective studies with concurrent control were eligible for the evidence synthesis. The quality of the individual studies and the strength of the available evidence were assessed using the Cochrane risk of bias tool and the Grading of Recommendations, Assessment, Development, and Evaluation approach, respectively. For the preventive treatment of extracorporeal cytokine adsorption therapy in patients undergoing cardiac surgery, we found very low-quality inconclusive evidence for mortality (five randomized controlled trials, n = 163), length of stay in the ICU (five randomized controlled trials, n = 163), and length of hospitalization (three randomized controlled trials, n = 101). Very low-quality inconclusive evidence was found for (serious) adverse events (four randomized controlled trials, n = 148). For the therapeutic treatment of extracorporeal cytokine adsorption therapy in patients with sepsis/septic shock, we found very low-quality inconclusive evidence for mortality up to 60-day follow-up (two randomized controlled trials, n = 117), organ function (two randomized controlled trials, n = 117) and length of stay in the ICU (one randomized controlled trial, n = 20). Very low-quality inconclusive evidence was found for (serious) adverse events (two randomized controlled trials, n = 117). Conclusions: Given the available evidence, the efficacy and safety of extracorporeal cytokine adsorption therapy in combination with standard care in the investigated indications was not established. We strongly recommend considering well-powered studies with patient-relevant endpoints instead of investing further research funds on studies that may not shed light on the clinical benefit of extracorporeal cytokine adsorption 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). The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: gregor.goetz@aihta.at Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: To describe study design considerations and to simulate a trial of biomarker-guided sepsis management aimed to reduce acute kidney injury (acute kidney injury). Tissue inhibitor of metalloproteinases-2 and insulin-like growth factor-binding protein 7 , urinary biomarkers of cell-cycle arrest, and indicators of kidney stress can detect acute kidney injury before clinical manifestations. We sought to determine the event rates for acute kidney injury as a function of serial measurements of urinary (tissue inhibitor of metalloproteinases-2)•(insulin-like growth factor-binding protein 7) in patients at risk of sepsis-associated acute kidney injury, so that an escalating series of kidney-sparing sepsis bundles based on international guidelines could be applied. Design: We described the study protocol of “Limiting acute kidney injury Progression In Sepsis,” a phase 4, multicenter, adaptive, randomized controlled trial. We performed simulations to estimate the rates for the trial’s primary endpoint using patient-level data from two previous studies (Sapphire and Protocolized Care for Early Septic Shock). Setting: Academic and community ICUs. Patients: Critically ill patients with sepsis or septic shock, without evidence of stage 2/3 acute kidney injury at enrollment. Interventions: None. Measurements and Main Results: Our primary endpoint is progression of two or more stages of acute kidney injury, death, or dialysis within 72 hours after enrollment. In the Sapphire simulation, 45 of 203 patients (22%) with sepsis met the endpoint. In Protocolized Care for Early Septic Shock, 144 of 607 patients (24%) with septic shock met the endpoint. In both simulations, (tissue inhibitor of metalloproteinases-2)•(insulin-like growth factor-binding protein 7) patterns, suggested by Limiting acute kidney injury Progression In Sepsis protocol, stratified the risk for the endpoint from 6% (three negative tests) to 41% (for patients eligible for the highest level of kidney-sparing sepsis bundle) in Sapphire, and 14% (two negative tests) to 46% (for the highest level of kidney-sparing sepsis bundle) in Protocolized Care for Early Septic Shock. Conclusions: Findings of our Limiting acute kidney injury Progression In Sepsis trial simulation confirmed that (tissue inhibitor of metalloproteinases-2)•(insulin-like growth factor-binding protein 7) could identify patients with different rates of progression to moderate/severe acute kidney injury, death, or dialysis in 72 hours. The Limiting acute kidney injury Progression In Sepsis protocol algorithm is therefore feasible in terms of identifying suitably high-risk individuals for kidney-sparing sepsis bundle. This work was performed at the University of Pittsburgh, Pittsburgh, PA. Available at ClinicalTrials.gov number NCT04434209. Institutional Review Board Approval Number: STUDY19050005. A complete list of Sapphire and ProCESS Investigators is provided in the Supplemental Digital Content (http://links.lww.com/CCM/G472). 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 bioMérieux SA, Marcy l’Etoile, France. Drs. Heskia, Ronco, Guzzi, Toback, Birch, Beyhaghi, Kwan, Kampf, and Kellum received funding from bioMérieux. Drs. Heskia, Toback, Birch, Beyhaghi, Kwan, and Kampf are current or former employees of bioMérieux. Drs. Heskia and Birch disclosed the off-label product use of Astute NephroCheck Test. Drs. Ronco, Guzzi, and Kellum are paid consultants for bioMérieux and members of the steering committee for the Limiting acute kidney injury Progression In Sepsis trial. Drs. Kwan and Kampf received funding from Astute Medical, Inc. Dr. Yealy’s institution received funding from the National Institute of General Medical Sciences; he 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: kellumja@upmc.edu This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: To examine the effect of premorbid β-blocker exposure on mortality and organ dysfunction in sepsis. Design: Retrospective observational study. Setting: ICUs in Australia, the Czech Republic, and the United States. Patients: Total of 4,086 critical care patients above 18 years old with sepsis between January 2014 and December 2018. Intervention: Premorbid beta-blocker exposure. Measurements and Main Results: One thousand five hundred fifty-six patients (38%) with premorbid β-blocker exposure were identified. Overall ICU mortality rate was 15.1%. In adjusted models, premorbid β-blocker exposure was associated with decreased ICU (adjusted odds ratio, 0.80; 95% CI, 0.66–0.97; p = 0.025) and hospital (adjusted odds ratio, 0.83; 95% CI, 0.71–0.99; p = 0.033) mortality. The risk reduction in ICU mortality of 16% was significant (hazard ratio, 0.84, 95% CI, 0.71–0.99; p = 0.037). In particular, exposure to noncardioselective β-blocker before septic episode was associated with decreased mortality. Sequential Organ Failure Assessment score analysis showed that premorbid β-blocker exposure had potential benefits in reducing respiratory and neurologic dysfunction. Conclusions: This study suggests that β-blocker exposure prior to sepsis, especially to noncardioselective β blockers, may be associated with better outcome. The findings suggest prospective evaluation of β-blocker use in the management of sepsis. Drs. K. Tan and Nalos contributed to design of study and writing of article. Drs. K. Tan, Harazim, Simpson, Gunawan, Whitehead, and Nalos contributed to study database development. Drs. K. Tan, Y. Tan, and Robledo contributed to review of study statistical code. Drs. Harazim, Tang, McLean, and Nalos contributed to design of study, writing, and review of 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 Nepean Institute of Critical Care Education and Research. Drs. K. Tan’s, Y. Tan’s, and Nalos’ institutions received funding from the Nepean Institute of Critical Care Education and Research. Dr. Nalos also received funding from the Charles Manuscript (All Manuscript Text Pages in MS Word format, including References and Figure Legends) University Research Fund and the Ministry of Youth and Education Services of the Czech Republic. Dr. Nalos is supported by the Charles University Research Fund (project number Q39) and by project number CZ.02.1.01/0.0/.0/16_019/0000787 “Fighting Infectious Diseases,” awarded by the Ministry of Youth and Education Services of the Czech Republic. The remaining authors have disclosed that there are no potential conflicts of interest. For information regarding this article, E-mail: mareknalos@gmail.com Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Infection and Immunity, <a href="https://journals.asm.org/toc/iai/89/6">Volume 89, Issue 6</a>, May 2021.

Antimicrobial resistance (particularly by extended spectrum β-lactamase and aminoglycoside modifying enzyme production) in neonatal sepsis is a global problem, particularly in low- and middle-income countries, causing significant mortality. High rates of resistance are reported for the current WHO-recommended first-line antibiotic regimen for neonatal sepsis; ampicillin and gentamicin. We assessed the utility of fosfomycin and amikacin as a potential alternative regimen to be used in settings of increasingly prevalent antimicrobial resistance. The combination was studied in a 16 arm dose ranged hollow-fiber infection model (HFIM) experiment. The combination of amikacin and fosfomycin enhanced bactericidal activity and prevented emergence of resistance compared to monotherapy of either antibiotic. Modelling of the experimental quantitative outputs and data from checkerboard assays, indicated synergy. We further assessed the combination regimen at clinically relevant doses in HFIM with nine Enterobacterales strains with high fosfomycin/amikacin MICs and demonstrated successful kill to sterilisation in 6/9 strains. From these data, we propose a novel combination breakpoint threshold for microbiological success for this antimicrobial combination against Enterobacterales - MICF * MICA < 256 (where MICF and MICA are MICs for fosfomycin and amikacin). Monte Carlo simulations predict that a standard fosfomycin/amikacin neonatal regimen will achieve a >99% probability of pharmacodynamic success for strains with MICs below this threshold. We conclude that the combination of fosfomycin with amikacin is a viable regimen for the empiric treatment of neonatal sepsis and is suitable for further clinical assessment in a randomised controlled trial.

Antimicrobial Agents and Chemotherapy, <a href="https://journals.asm.org/toc/aac/0/ja">Volume 0, Issue ja</a>, -Not available-.

by Xing Song, Mei Liu, Lemuel R. Waitman, Anurag Patel, Steven Q. Simpson Purpose To understand what clinical presenting features of sepsis patients are historically associated with rapid treatment involving antibiotics and fluids, as appropriate. Design This was a retrospective, observational cohort study using a machine-learning model with an embedded feature selection mechanism (gradient boosting machine). Methods For adult patients (age ≥ 18 years) who were admitted through Emergency Department (ED) meeting clinical criteria of severe sepsis from 11/2007 to 05/2018 at an urban tertiary academic medical center, we developed gradient boosting models (GBMs) using a total of 760 original and derived variables, including demographic variables, laboratory values, vital signs, infection diagnosis present on admission, and historical comorbidities. We identified the most impactful factors having strong association with rapid treatment, and further applied the Shapley Additive exPlanation (SHAP) values to examine the marginal effects for each factor. Results For the subgroups with or without fluid bolus treatment component, the models achieved high accuracy of area-under-receiver-operating-curve of 0.91 [95% CI, 0.86-0.95] and 0.84 [95% CI, 0.81-0.86], and sensitivity of 0.81[95% CI, 0.72-0.87] and 0.91 [95% CI, 0.81-0.97], respectively. We identified the 20 most impactful factors associated with rapid treatment for each subgroup. In the non-hypotensive subgroup, initial physiological values were the most impactful to the model, while in the fluid bolus subgroup, value minima and maxima tended to be the most impactful. Conclusion These machine learning methods identified factors associated with rapid treatment of severe sepsis patients from a large volume of high-dimensional clinical data. The results provide insight into differences in the rapid provision of treatment among patients with sepsis.

by Osvaldo Ulises Garay, Gonzalo Guiñazú, Wanda Cornistein, Javier Farina, Ricardo Valentini, Gabriel Levy Hara Background Inappropriate antibiotic use represents a major global threat. Sepsis and bacterial lower respiratory tract infections (LRTIs) have been linked to antimicrobial resistance, carrying important consequences for patients and health systems. Procalcitonin-guided algorithms may represent helpful tools to reduce antibiotic overuse but the financial burden is unclear. The aim of this study was to estimate the healthcare and budget impact in Argentina of using procalcitonin-guided algorithms to guide antibiotic prescription. Methods A decision tree was used to model health and cost outcomes for the Argentinean health system, over a one-year duration. Patients with suspected sepsis in the intensive care unit and hospitalized patients with LRTI were included. Model parameters were obtained from a focused, non-systematic, local and international bibliographic search, and validated by a panel of local experts. Deterministic and probabilistic sensitivity analyses were performed to analyze the uncertainty of parameters. Results The model predicted that using procalcitonin-guided algorithms would result in 734.5 [95% confidence interval (CI): 1,105.2;438.8] thousand fewer antibiotic treatment days, 7.9 [95% CI: 18.5;8.5] thousand antibiotic-resistant cases avoided, and 5.1 [95% CI: 6.7;4.2] thousand fewer Clostridioides difficile cases. In total, this would save $422.4 US dollars (USD) [95% CI: $935;$267] per patient per year, meaning cost savings of $83.0 [95% CI: $183.6;$57.7] million USD for the entire health system and $0.4 [95% CI: $0.9;$0.3] million USD for a healthcare provider with 1,000 cases per year of sepsis and LRTI patients. The sensitivity analysis showed that the probability of cost-saving for the sepsis patient group was lower than for the LRTI patient group (85% vs. 100%). Conclusions Healthcare and financial benefits can be obtained by implementing procalcitonin-guided algorithms in Argentina. Although we found results to be robust on an aggregate level, some caution must be used when focusing only on sepsis patients in the intensive care unit.

The effect of the timing of norepinephrine initiation on clinical outcomes in patients with septic shock is uncertain. A systematic review and meta-analysis was performed to evaluate the impact of early and late start of norepinephrine support on clinical outcomes in patients with septic shock.

Although early antimicrobial discontinuation guided by procalcitonin (PCT) has shown decreased antibiotic consumption in lower respiratory tract infections, the outcomes in long-term sepsis sequelae remain unclear. To investigate if PCT guidance may reduce the incidence of long-term infection-associated adverse events in sepsis. In this multicenter trial, 266 patients with sepsis (by Sepsis-3 definitions) with lower respiratory tract infections, acute pyelonephritis, or primary bloodstream infection were randomized (1:1) to receive either PCT-guided discontinuation of antimicrobials or standard of care. The discontinuation criterion was ≥80% reduction in PCT levels or any PCT ≤0.5 μg/L at Day 5 or later. The primary outcome was the rate of infection-associated adverse events at Day 180, a composite of the incidence of any new infection by or multidrug-resistant organisms, or any death attributed to baseline or multidrug-resistant organism infection. Secondary outcomes included 28-day mortality, length of antibiotic therapy, and cost of hospitalization. The rate of infection-associated adverse events was 7.2% (95% confidence interval [CI], 3.8-13.1%; 9/125) versus 15.3% (95% CI, 10.1-22.4%; 20/131) (hazard ratio, 0.45; 95% CI, 0.20-0.98;  = 0.045); 28-day mortality 15.2% (95% CI, 10-22.5%; 19/125) versus 28.2% (95% CI, 21.2-36.5%; 37/131) (hazard ratio, 0.51; 95% CI, 0.29-0.89;  = 0.02); and median length of antibiotic therapy 5 (range, 5-7) versus 10 (range, 7-15) days ( < 0.001) in the PCT and standard-of-care arms, respectively. The cost of hospitalization was also reduced in the PCT arm. In sepsis, PCT guidance was effective in reducing infection-associated adverse events, 28-day mortality, and cost of hospitalization.Clinical trial registered with www.clinicaltrials.gov (NCT03333304).

Sepsis is life-threatening organ dysfunction due to a dysregulated host response to infection. It is considered a major cause of health loss, but data for the global burden of sepsis are limited. As a syndrome caused by underlying infection, sepsis is not part of standard Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) estimates. Accurate estimates are important to inform and monitor health policy interventions, allocation of resources, and clinical treatment initiatives. We estimated the global, regional, and national incidence of sepsis and mortality from this disorder using data from GBD 2017.

Procalcitonin (PCT)-guided antibiotic discontinuation appears to decrease antibiotic use in critically ill patients, but its impact on survival remains less certain.

Comparative clinical effects of balanced crystalloids and saline are uncertain, particularly in noncritically ill patients cared for outside an intensive care unit (ICU).

Both balanced crystalloids and saline are used for intravenous fluid administration in critically ill adults, but it is not known which results in better clinical outcomes.

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.

We assessed the effects of a protocol restricting resuscitation fluid vs. a standard care protocol after initial resuscitation in intensive care unit (ICU) patients with septic shock.

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.

For patients in intensive care units, sepsis is a common and potentially deadly complication and prompt initiation of appropriate antimicrobial therapy improves prognosis. The objective of this trial was to determine whether a strategy of antimicrobial spectrum escalation, guided by daily measurements of the biomarker procalcitonin, could reduce the time to appropriate therapy, thus improving survival.

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.