Sepsis

Clinical & Experimental Immunology, Accepted Article.

Abstract In patients who develop sepsis, whether due to primary, secondary or metastatic lesions, the skin is frequently affected. However, there are unresolved aspects regarding the general clinical manifestations in the skin or the prognosis and/or therapeutic implications. The main challenge in the approach to sepsis is its early diagnosis and management. In this review, we address the sepsis–skin relationship and the potential impact of early dermatological intervention on the septic patient through ten basic questions. We found little evidence of the participation of the dermatologist in sepsis alert programs. There are early skin changes that may alert clinicians on a possible sepsis, such as skin mottling or variations in acral skin temperature. In addition, the skin is an accessible and highly cost-effective tissue for etiological studies of some forms of sepsis (e.g., meningococcal purpura) and its involvement defines the prognosis of certain patients (e.g., infective endocarditis).

The updated national Dutch Working Party on Antibiotic Policy (SWAB) guideline for antibacterial therapy of adult patients with sepsis recommends against the addition of an aminoglycoside to a beta-lactam agent for patients with sepsis or septic shock unless local distribution of pathogens associated with sepsis and their antimicrobial susceptibilities justify its additional use. [1] However, this data is generally not readily available and adjunctive gentamicin is often given. From an antimicrobial stewardship perspective, we evaluated our local sepsis protocol by assessing the potential benefit and risk of gentamicin adjunctive to cefuroxime by studying blood culture results and incidence of acute kidney injury (AKI).

Objectives: We investigated the prevalence of pre- and postsepsis depression and examined the association between diagnosis of pre- and postsepsis depression and 5-year all-cause mortality among survivors of sepsis. Design: A population-based cohort study. Setting: Data were obtained from the National Health Insurance Service database in South Korea. Patients: Sepsis survivors were defined as those who were admitted with a main diagnosis of sepsis or septic shock and had survived for over 365 days. Measurements and Main Results: Sepsis survivors who were diagnosed with depression before sepsis were defined as the presepsis depression group, whereas those who had no history of depression but were newly diagnosed with depression within 1 year of diagnosis of sepsis were defined as the postsepsis depression group. All other participants comprised the control group. A total of 45,826 sepsis survivors were included in the final analysis. Among the survivors, 1,105 (2.4%) were in the postsepsis depression group, whereas 9,626 (21.0%) were in the presepsis depression group. The 5-year all-cause mortality rate in the pre- and postsepsis depression group was 44.1% and 46.2%, whereas that in the control group was 30.4%. Multivariable Cox regression modeling revealed that the risk of 5-year all-cause mortality rate in the postsepsis depression group was 1.29-fold (hazard ratio = 1.29; 95% CI = 1.18–1.41; p < 0.001) higher than that of the control group, whereas the presepsis depression group was not significantly associated with 5-year all-cause mortality (p = 0.509). Conclusions: Among sepsis survivors in South Korea, 2.4%% were newly diagnosed with depression within 1 year after their sepsis diagnosis. In addition, postsepsis depression was independently associated with higher 5-year all-cause mortality among sepsis survivors. Our results suggest that patients with a history of sepsis and associated depression may be a high-risk group that interventions may be directed toward. 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: songoficu@outlook.kr Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: Sepsis is a life-threatening condition and is one of the leading causes of death in the United States. The burden of sepsis-related mortality in the United States in recent years is not well characterized. We sought to describe sepsis-related mortality rates and mortality trends in the United States from 2005 to 2018. Design: Retrospective population-based study. Setting: We used the Multiple Cause of Death Database available through the Centers for Disease Control and Prevention website. Patients: Decedents with sepsis-related deaths were identified using previously validated International Classification of Diseases codes. Interventions: None. MEASUREMENTS AND Main Results: From 2005 to 2018, 6.7% of decedents had a diagnosis of sepsis. The overall sepsis-related mortality rates remained stable in both males (57 deaths per 100,000) and females (45.1 deaths per 100,000) during this period. Compared with Whites, the sepsis-related mortality rates were higher in Blacks (rate ratio = 1.78), Native Americans (rate ratio = 1.43), and Hispanics (rate ratio = 1.04) and were lower in Asians (rate ratio = 0.73). Sepsis-related mortality rates declined in Blacks, Hispanics, and Asians but increased in Whites and Native Americans. The majority of sepsis-related deaths occurred in the hospital. The percentage of deaths in the nursing home decreased, whereas deaths occurring at home and hospice increased. Conclusions: From 2005 to 2018, the overall sepsis-related mortality rates were stable, but there were significant racial and gender disparities in mortality trends. Further research is needed to evaluate the genetic and environmental contributors to these differences. 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: njeganathan@llu.edu Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Purpose of review Biomarkers, mainly procalcitonin, are commonly used in sepsis diagnosis, prognosis and treatment follow-up. This review summarizes the potential benefit of their use for the critically ill. Recent findings Increased clinical evidence from randomized clinical trials of biomarker-guided treatment suggests a trend for appropriate but short antimicrobial treatment for the critically ill. Procalcitonin (PCT) is the most studied biomarker; in the majority of randomized clinical trials, the use of a stopping rule of antibiotics on the day when PCT is below 80% from baseline or less than 0.5 ng/ml was proven effective to reduce length of antimicrobial treatment, antibiotic-associated adverse events and infectious complications like infections by multidrug-resistant organisms and Clostridium difficile. Survival benefit was also noted. Summary Biomarkers, mainly PCT, may help improve sepsis outcome by restriction of injudicious antimicrobial use.

Abstract Background The primary objective of our study was to examine predictors for readmission in a prospective cohort of sepsis patients admitted to an emergency department (ED) and identified by the new Sepsis-3 criteria. Method A single-center observational population-based cohort study among all adult (≥18 years) patients with sepsis admitted to the emergency department of Slagelse Hospital during 1.10.2017–31.03.2018. Sepsis was defined as an increase in the sequential organ failure assessment (SOFA) score of ≥2. The primary outcome was 90-day readmission. We followed patients from the date of discharge from the index admission until the end of the follow-up period or until the time of readmission to hospital, emigration or death, whichever came first. We used competing-risks regression to estimate adjusted subhazard ratios (aSHRs) with 95% confidence intervals (CI) for covariates in the regression models. Results A total of 2110 patients were admitted with infections, whereas 714 (33.8%) suffered sepsis. A total of 52 patients had died during admission and were excluded leaving 662 patients (44.1% female) with a median age of 74.8 (interquartile range: 66.0–84.2) years for further analysis. A total of 237 (35,8%; 95% CI 32.1–39.6) patients were readmitted within 90 days, and 54(8.2%) had died after discharge without being readmitted. We found that a history of malignant disease (aSHR 1,61; 1.16–2.23), if previously admitted with sepsis within 1 year before the index admission (aSHR; 1.41; 1.08–1.84), and treatment with diuretics (aSHR 1.51; 1.17–1.94) were independent predictors for readmission. aSHR (1.49, 1.13–1.96) for diuretic treatment was almost unchanged after exclusion of patients with heart failure, while aSHR (1.47, 0.96–2.25) for malignant disease was slightly attenuated after exclusion of patients with metastatic tumors. Conclusions More than one third of patients admitted with sepsis, and discharged alive, were readmitted within 90 days. A history of malignant disease, if previously admitted with sepsis, and diuretic treatment were independent predictors for 90-day readmission.

Immune paralysis is a protracted state of immune suppression following the early/acute inflammatory phase of sepsis. CD11b+Gr-1+ cells induced during sepsis are heterogeneous myeloid-derived cells (MDCs). This study investigated the contribution of MDCs to immune paralysis. Treatment of mice with zymosan (ZM) induced a marked increase in the total number of splenocytes with an increase in the ratio of Gr-1hi cells and a decease in the ratio of T cells on day 7, eventually returning to levels similar to those of control mice on day 21. T cell activation and IFN- expression by CD8+ T cells were clearly impaired in ZM-treated mice on day 21 (d21-ZM mice). Gr-1hi cells showed a CD11b+Ly6Ghi polymorphonuclear phenotype. Injection of lipopolysaccharide (LPS) into d21-ZM mice impaired IL-6 production in serum, accompanied by accumulation of CD11b+Gr-1hi cells in the peripheral blood. Transfer of Gr-1hi cells from d21-ZM mice into intact mice impaired IL-6 production, but similar transfer of Gr-1hi cells from PD-1/PD-L1-deficient d21-ZM mice showed no such suppressive effect. Conversely, either depletion of Gr-1hi cells by treatment with anti-Gr-1 monoclonal antibody (mAb) or neutralization of the PD-1/PD-L1 pathway by anti-PD-1 and anti-PD-L1 mAbs during the induction phase of sepsis ameliorated ZM-induced immune suppression. Our results suggest that the PD-1/PD-L1-mediated generation of Gr-1hi cells in the early phase of sepsis is required for late-phase of immune paralysis.

Background: Accelerate Pheno system and BacT/ALERT VIRTUO may improve bacteremia management. This study evaluated the impact of both devices on outcomes in patients with sepsis and concurrent gram-negative bacteremia. Methods: This quasi-experimental study included a retrospective pre-implementation and a prospective post-implementation group. Patients ≥18 years old with gram-negative bacteremia were included. Patients with neutropenia, pregnancy, were transferred from an outside hospital with active bloodstream infection, or polymicrobial bacteremia were excluded. Blood culture incubation in the BacT/ALERT 3D and microdilution antimicrobial susceptibility testing from culture plate growth was used prior to implementation of BacT/ALERT VIRTUO and Accelerate Pheno. MALDI-TOF identification directly from blood culture was used pre- and post-implementation. Time to gram-stain, identification, susceptibility reporting, initiation of narrow spectrum gram-negative therapy at 72 hours, 30-day inpatient mortality, sepsis resolution, and hospital length of stay were evaluated. Results: 116 patients were included (63 pre-implementation, 53 post-implementation). Median time to gram-stain and susceptibility results were significantly shorter post-implementation (P < 0.001). The post-implementation group had an improved hazard for narrow spectrum gram-negative therapy at 72 hours (HR [95% CI] = 2.685 [1.348 – 5.349]), reduced hazard for 30-day inpatient mortality (aHR: 0.150 [0.026 – 0.846]) and improved sepsis resolution (77.8% vs. 92.5%, P = 0.030). Hospital length of stay was unchanged between groups. Conclusion: The implementation of BacT/Alert VIRTUO and the Accelerate Pheno system improved microbiology laboratory processes, antibiotic utilization processes and clinical outcomes. These data support the use of rapid diagnostics in sepsis with concurrent gram-negative bacteremia.

Purpose The Mid-German Sepsis Cohort (MSC) aims to investigate mid-term and long-term functional disabilities in sepsis survivors from intensive care unit (ICU) discharge until 1 year after. Secondary, post-acute mortality and morbidity, health-related quality of life and healthcare utilisation will be investigated. Participants The MSC comprises adult (aged ≥18 years) patients who were treated for (severe) sepsis or septic shock on ICU. The participants were recruited between 15 April 2016 and 30 November 2018 from five German centres. Three thousand two hundred and ten patients with sepsis were identified, of which 1968 survived their ICU stay and were eligible for enrolment in the follow-up cohort. Informed consent for follow-up assessment was provided by 907 patients (46.1% of eligible patients). Findings to date The recruitment of the participants for follow-up assessments and the baseline data collection is completed. Incidence of sepsis was 116.7 patients per 1000 ICU patients. In this cohort profile, we provide an overview of the demographics and the clinical characteristics of both the overall sepsis cohort and the ICU survivors who provided informed consent for follow-up assessment (907 out of 1968 ICU survivors (46.1%)). Future plans The follow-ups are conducted 3, 6 and 12 months after ICU discharge. Another yearly follow-up up to 5 years after ICU discharge is pursued. Several cooperation and satellite projects were initiated. This prospective cohort offers a unique resource for research on long-term sequelae of sepsis survivors. Trial registration number German Clinical Trials Registry (DRKS00010050).

No abstract available…

Objective The quick Sequential Organ Failure Assessment (qSOFA) is developed as a tool to identify patients with infection with increased risk of dying from sepsis in non-intensive care unit settings, like the emergency department (ED). An abnormal score may trigger the initiation of appropriate therapy to reduce that risk. This study assesses the risk of a treatment paradox: the effect of a strong predictor for mortality will be reduced if that predictor also acts as a trigger for initiating treatment to prevent mortality. Design Retrospective analysis on data from a large observational cohort. Setting ED of a tertiary medical centre in the Netherlands. Participants 3178 consecutive patients with suspected infection. Primary outcome To evaluate the existence of a treatment paradox by determining the influence of baseline qSOFA on treatment decisions within the first 24 hours after admission. Results 226 (7.1%) had a qSOFA ≥2, of which 51 (22.6%) died within 30 days. Area under receiver operating characteristics of qSOFA for 30-day mortality was 0.68 (95% CI 0.61 to 0.75). Patients with a qSOFA ≥2 had higher odds of receiving any form of intensive therapy (OR 11.4 (95% CI 7.5 to 17.1)), such as aggressive fluid resuscitation (OR 8.8 95% CI 6.6 to 11.8), fast antibiotic administration (OR 8.5, 95% CI 5.7 to 12.3) or vasopressic therapy (OR 17.3, 95% CI 11.2 to 26.8), compared with patients with qSOFA <2. Conclusion In ED patients with suspected infection, a qSOFA ≥2 was associated with more intensive treatment. This could lead to inadequate prediction of 30-day mortality due to the presence of a treatment paradox. Trial registration number 6916.

OBJECTIVE: Expand upon the priorities of fluid resuscitation and vasopressor therapy research priorities identified by a group of experts assigned by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. DATA SOURCES: Original article, literature search. STUDY SELECTION: Several members of the original task force with expertise specific to the area of fluid resuscitation and vasopressor therapy. DATA EXTRACTION: None. DATA SYNTHESIS: None. CONCLUSION: In the second of a series of manuscripts subsequent to the original article, members with expertise in the subjects expound upon the three identified priorities related to fluid resuscitation and vasopressor therapies. This analysis summarizes what is known and what were identified as ongoing and future research. This article is being published simultaneously in Intensive Care Medicine Experimental. DOI: 10.1186/s40635-021-00369-9 Members of the Surviving Sepsis Campaign Research Committee are listed in the Appendix. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: ilat@sralab.org 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: Worldwide, more than half of all sepsis cases occur in pediatric and adolescent patients, particularly in neonates. Previous population-based studies in these age groups often were limited to either neonatal or pediatric patients admitted to ICUs. We aimed to investigate the overall and age-specific incidence and case fatality of sepsis in children in Germany, a high-income country with a total population of 82 million. Design: Retrospective observational study based on the German Diagnosis-related Groups statistics of the years 2010–2016. Setting: All acute care hospitals in Germany except for prison and psychiatric hospitals. Patients: Pediatric patients less than or equal to 19 years with International Classification of Diseases, 10th Revision-coded sepsis, neonates with International Classification of Diseases, 10th Revision-coded neonatal sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed pediatric sepsis incidence in patients aged birth to less than or equal to 19 years old, case fatality, and underlying comorbidities, and neonatal sepsis incidence and case fatality within the neonatal period. We identified 14,635 pediatric sepsis cases among 15.4 million pediatric hospitalizations between 2010 and 2016 (= 0.1% of pediatric hospitalizations). The incidence of pediatric sepsis was 14 cases per 100,000 children between 0 and 19 years. Case fatality was 16.6% and decreased from 17.8% (2010) to 15.0% (2016). A total of 11.5% of hospital deaths in the age group 0–19 years were associated with pediatric sepsis. Sepsis incidence and case fatality were highest in children less than 1 year old and declined in older children and adolescents. Admissions with pediatric sepsis were more common in children with preexisting comorbidities compared with those without (0.52% vs 0.03% of pediatric admissions). In neonates, the incidence of neonatal sepsis was 1,006 cases per 100,000 live births. Case fatality was 3.9%. While 17.7% of very low birth weight infants had neonatal sepsis, only 2.1% of low birth weight and 0.6% of normal birth weight neonates were affected, respectively. Conclusions: Sepsis is also in Germany a common and frequently fatal condition in pediatric patients, particularly among neonates and children with comorbidities. The data of the Diagnosis-Related Group statistics, which is used in this study, are owned by the Federal Statistical Office and were analyzed by remote data processing. To use the data, a data use contract has to be established with the Federal Statistical Office. Thus, we cannot grant access to the data used in this study. Drs. Born, Reinhart, and Fleischmann-Struzek designed the study. Dr. Matthäus-Krämer, Dr. Reichert, Ms. Schettler, and Dr. Fleischmann-Struzek defined International Classification of Diseases (ICD)-based identification criteria and translated the Pediatric Complex Chronic Conditions ICD, 10th Revision, Clinical Modification codes. Dr. Born conducted the statistical analyses. Drs. Born and Fleischmann-Struzek drafted the article. The remaining authors contributed to the interpretation and discussion of the data as well as sections of the article and approved its final version. 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: Carolin.Fleischmann@med.uni-jena.de Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: Cognitive impairment is an important consequence of sepsis. We sought to determine long-term trajectories of cognitive function after sepsis. Design: Prospective study of the Reasons for Geographic and Racial Differences in Stroke cohort. Setting: United States. Patients: Twenty-one thousand eight-hundred twenty-three participants greater than or equal to 45 years, mean (SD) age 64.3 (9.2) years at first cognitive assessment, 30.9% men, and 27.1% Black. Measurements and Main Results: The main exposure was time-dependent sepsis hospitalization. The primary outcome was global cognitive function (Six-Item Screener range, 0–6). Secondary outcomes were incident cognitive impairment (Six-Item Screener score ≤ 4 [impaired] vs ≥5 [unimpaired]), new learning (Consortium to Establish a Registry for Alzheimer Disease Word List Learning range, 0–30), verbal memory (word list delayed recall range, 0–10), and executive function/semantic fluency (animal fluency test range, ≥ 30). Over a median follow-up of 10 years (interquartile range, 6–12 yr), 840 (3.8%) experienced sepsis (incidence 282 per 1,000 person-years). Sepsis was associated with faster long-term declines in Six-Item Screener (–0.02 points per year faster [95% CI, –0.01 to –0.03]; p < 0.001) and faster long-term rates of incident cognitive impairment (odds ratio 1.08 per year [95% CI, 1.02–1.15]; p = 0.008) compared with presepsis slopes. Although cognitive function acutely changed after sepsis (0.05 points [95% CI, 0.01–0.09]; p = 0.01), the odds of acute cognitive impairment (Six-Item Screener ≤ 4) immediately after sepsis was not significant (odds ratio, 0.81 [95% CI, 0.63–1.06]; p = 0.12). Sepsis hospitalization was not associated with acute changes or faster declines in word list learning, word list delayed recall, or animal fluency test. Conclusions: Sepsis is associated with accelerated long-term decline in global cognitive function. Current affiliation for Dr. Wang: Department of Emergency Medicine, The Ohio State University, Columbus, OH. 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 full list of participating Reasons for Geographic And Racial Differences in Stroke investigators and institutions and institutions can be found at http://www.regardsstudy.org. Drs. Wang and Levine conceived the study. Drs. Wang and Safford obtained funding. Drs. Wang and Safford oversaw data collection. Mr. Kabeto conducted the analysis. Dr. Wang drafted the article and all authors contributed to its critical review. Mr. Kabeto had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Dr. Wang assumes overall responsibility for the article. Supported, in part, by award R01-NR012726 from the National Institute for Nursing Research, UL1-RR025777 from the National Center for Research Resources, as well as by grants from the Center for Clinical and Translational Science and the Lister Hill Center for Health Policy of the University of Alabama at Birmingham. The parent Reasons for Geographic And Racial Differences in Stroke research project is supported by a cooperative agreement U01-NS041588 from the National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Department of Health and Human Service. Dr. Wang’s institution received funding from the National Institutes of Health (NIH) National Institute of Nursing Research. Drs. Wang, Wadley, Muntner, Judd, Safford, and Levine received support for article research from the NIH. Dr. Safford reports the following potential conflicts of interest: Amgen—salary support to study patterns of statin use in Medicare and other large databases; diaDexus—salary support for a research grant on lipids and cardiovascular disease outcomes; diaDexus—consulting to help with U.S. Food and Drug Administration application; NIH, Agency for Healthcare Research and Quality (AHRQ)—salary support for research grants. Drs. Wadley’s and Judd’s institutions received funding from the NIH. Dr. Safford’s institution received funding from Amgen. Dr. Kempker’s institution received funding from AHRQ, and he received funding from Grifols; and he received support (K08HS025240) for article research from AHRQ. Dr. Levine’s institution received funding from National Institute on Aging and National Institute of Neurological Disorders and Stroke, and he disclosed government work. The remaining authors have disclosed that they do not have any potential conflicts of interest. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurologic Disorders and Stroke or the National Institutes of Health. Representatives of the funding agency have been involved in the review of the article but not directly involved in the collection, management, analysis, or interpretation of the data. For information regarding this article, E-mail: henry.wang@osumc.edu Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Sepsis is defined as a dysregulated host response to infection that leads to life-threatening acute organ dysfunction. It afflicts approximately 50 million people worldwide annually and is often deadly, even when evidence-based guidelines are applied promptly. Many randomized trials tested therapies for sepsis over the past 2 decades, but most have not proven beneficial. This may be because sepsis is a heterogeneous syndrome, characterized by a vast set of clinical and biologic features. Combinations of these features, however, may identify previously unrecognized groups, or “subclasses” with different risks of outcome and response to a given treatment. As efforts to identify sepsis subclasses become more common, many unanswered questions and challenges arise. These include: 1) the semantic underpinning of sepsis subclasses, 2) the conceptual goal of subclasses, 3) considerations about study design, data sources, and statistical methods, 4) the role of emerging data types, and 5) how to determine whether subclasses represent “truth.” We discuss these challenges and present a framework for the broader study of sepsis subclasses. This framework is intended to aid in the understanding and interpretation of sepsis subclasses, provide a mechanism for explaining subclasses generated by different methodologic approaches, and guide clinicians in how to consider subclasses in bedside care. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health and social care. The funding source did not have any role in the design, conduct or interpretation of study results. Dr. Seymour helped in designing the concept. Drs. DeMerle, Angus, and Seymour helped in designing. Drs. DeMerle, Baille, Brant, Calfee, Carcillo, Chang, Dickson, Evans, Gordon, Kennedy, Knight, Lindsell, Liu, Marshall, Randolph, Scicluna, Shankar-Hari, Shapiro, Sweeney, Talis, Tang, Thompson, Tsalik, van der Poll, van Vught, Wong, Yende, Zhao, and Seymour drafted the article and critically revised the article for important intellectual content. 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. DeMerle’s institution received funding from R35 GM119519-03 and T32HL007820. Dr. Calfee is supported in part by grants from the National Institutes of Health (NIH; HL140026). Dr. Carcillo is supported in part by grants from the National Institutes of Health (R01GM108618). Dr. DeMerle is supported in part by grants from the National Institutes of Health (T32HL007820). Dr. Angus received funding from Ferring Pharmaceuticals, Bristol-Myers Squibb, Bayer AG, and Alung Technologies. Drs. Angus, Brant, Carcillo, Chang, Dickson, Kennedy, Lindsell, Liu, Randolph, Thompson, Tsalik, Wong, and Seymour received support for article research from the NIH. Dr. Baillie received support for article research from Wellcome Trust/Charity Open Access Fund (COAF), and Research Councils UK. Dr. Calfee’s institution received funding from Roche/Genentech and Bayer, and she received funding from Roche/Genentech, Quark, CSL Behring, Bayer, Gen1e Life Sciences, and Vasomune. Drs. Carcillo’s and Seymour’s institutions received funding from the National Institute of General Medical Sciences. Drs. Chang’s, Lindsell’s, Liu’s, Randolph’s, Shapiro’s, and Wong’s institutions received funding from the NIH. Dr. Gordon’s institution received funding from the National Institute for Health Research (NIHR) Research Professorship (RP-2015-06-18), NIHR Imperial Biomedical Research Centre, GlaxoSmithKline, and Bristol Myers Squibb. Dr. Knight received support for article research from Wellcome Trust/COAF. Dr. Lindsell’s institution received funding from the Centers for Disease Control and Prevention (CDC), Department of Defense, Marcus Foundation, Entegrion, Endpoint Health, and bioMerieux, and he disclosed he is a coinventor on patents related to risk stratification in septic shock. Dr. Marshall received funding from AM Pharma, AKPA Pharma, and the Society of Critical Care Medicine (Critical Care Medicine Associate Editor). Dr. Randolph’s institution received funding from the CDC, and she received funding from La Jolla Pharma. Dr. Shapiro’s institution received funding from rapid pathogen screening, Baxter, and Inflammatix, and he received funding from Diagnostic Robotics. Dr. Sweeney received funding from Inflammatix. Dr. Thompson’s institution received funding from the National Heart, Lung, and Blood Institute, and he received funding from Bayer and Thetis. Dr. Tsalik disclosed that he is a founder and holds equity in Predigen; he receives salary support from the Durham VA Healthcare System and Duke University; and he has received salary support and/or grant funding (paid to his university) from the NIH, DARPA, DTRA, Karius, and Sanofi US. Dr. Wong disclosed that he and his institutions hold U.S. patents for sepsis biomarkers. Dr. Yende received funding from serving as consultant for expert testimony and he disclosed government work. Dr. Knight is supported by a Wellcome Trust Investigator Award (204969/Z/16/Z) and the NIHR Oxford Biomedical Research Centre. Dr. Lindsell was supported in part by grants from the National Institutes of Health (R35GM126943, R01HL149422), a research grant to VUMC from Endpoint Health, and is also listed as co-inventor on patents for endotyping and risk-stratification in pediatric septic shock. Dr. Liu is supported in part by grants from the National Institutes of Health (R35GM128672). Dr. Marshall is supported in part by grants from the Canadian Institutes of Health Research. Dr. Randolph is supported in part by grants from the National Institutes of Health (R21HD095228). Dr. Shankar-Hari is supported by the National Institute for Health Research Clinician Scientist Award (CS-2016-16-011). Dr. Wong is supported in part by grants from the National Institutes of Health (R35 GM126943). Dr. Sweeney is an employee of, and shareholder in, Inflammatix. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: demerlekm@upmc.edu Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: Rapid delivery of antibiotics is a cornerstone of sepsis therapy, although time targets for specific components of antibiotic delivery are unknown. We quantified time intervals comprising the task of antibiotic delivery and evaluated the association between interval delays and hospital mortality among patients treated in the emergency department for suspected sepsis. Design: Retrospective cohort. Setting: Twelve hospitals in Southeastern United States from 2014 to 2017. Patients: Twenty-four thousand ninety-three encounters among 20,026 adults with suspected sepsis in 12 emergency departments. Measurements and Main Results: We divided antibiotic administration into two intervals: time from emergency department triage to antibiotic order (recognition delay) and time from antibiotic order to infusion (administration delay). We used generalized linear mixed models to evaluate associations between these intervals and hospital mortality. Median time from emergency department triage to antibiotic administration was 3.4 hours (interquartile range, 2.0–6.0 hr), separated into a median recognition delay (time from emergency department triage to antibiotic order) of 2.7 hours(interquartile range, 1.5–4.7 hr) and median administration delay (time from antibiotic order to infusion) of 0.6 hours (0.3–1.2 hr). Adjusting for other risk factors, both recognition delay and administration delay were associated with mortality, but pairwise comparison with a no-delay reference group was not significant for up to 6 hours of recognition delay or up to 1.5 hours of administration delay. Conclusions: Both recognition delays and administration delays were associated with increased hospital mortality, but only for longer delays. These results suggest that both metrics may be important to measure and improve for patients with suspected sepsis but do not support targets less than 1 hour. 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). Presented, in part, at the annual meeting of the Society Critical Care Medicine, San Antonio, TX, February 2018. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: Stephanie.p.taylor@atriumhealth.org Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: Septic cardiomyopathy develops frequently in patients with sepsis and likely increases short-term mortality. However, whether septic cardiomyopathy is associated with long-term outcomes after sepsis is unknown. We investigated whether septic patients with septic cardiomyopathy have worse long-term outcomes than septic patients without septic cardiomyopathy. Design: Retrospective cohort study. SETTING: Adult ICU. PATIENTS: Adult ICU patients with sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Left ventricular global longitudinal systolic strain was our primary measure of septic cardiomyopathy. We employed a suite of multivariable survival analyses to explore linear and nonlinear associations between left ventricular global longitudinal systolic strain and major adverse cardiovascular events, which included death, stroke, and myocardial infarction. Our primary outcome was major adverse cardiovascular event through 24 months after ICU discharge. Among 290 study patients, median left ventricular global longitudinal systolic strain was –16.8% (interquartile range, –20.4% to –12.6%), and 38.3% of patients (n = 111) experienced a major adverse cardiovascular event within 24 months after discharge. On our primary, linear analysis, there was a trend (p = 0.08) toward association between left ventricular global longitudinal systolic strain and major adverse cardiovascular event (odds ratio, 1.03; CI, < 1 to 1.07). On our nonlinear analysis, the association was highly significant (p < 0.001) with both high and low left ventricular global longitudinal systolic strain associated with major adverse cardiovascular event among patients with pre-existing cardiac disease. This association was pronounced among patients who were younger (age < 65 yr) and had Charlson Comorbidity Index greater than 5. Conclusions: Among patients with sepsis and pre-existing cardiac disease who survived to ICU discharge, left ventricular global longitudinal systolic strain demonstrated a U-shaped association with cardiovascular outcomes through 24 months. The relationship was especially strong among younger patients with more comorbidities. These observations are likely of use to design of future trials. 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 Intermountain Institutional Review Board approved this study with waiver of informed consent. Drs Beesley, Tonna, Paine, Grissom, and Brown designed the study. Drs. Beesley, Sorensen, Tonna, Paine, and Brown analyzed and interpreted the data. Dr. Beesley drafted the report, and all other authors revised it. All authors gave final approval of the report to be published. Supported (in part or in full) by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR001067. Dr. Walkey received funding from UptoDate. Dr. Tonna’s institution received funding from National Heart, Lung, and Blood Institute (NHLBI), National Center for Advancing Translational Sciences, and LivaNova; he received funding from Philips Healthcare; he received support for article research from National Institutes of Health; and he was supported by a career development award (K23HL141596) from the NHLBI of the National Institutes of Health. Dr. Burk received funding from Intermountain Research and Medical Foundation. Dr. Paine’s institution received funding from NHLBI and the Department of Veterans Affairs. The remaining authors have disclosed that they do not have any potential conflicts of interest. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. For information regarding this article, E-mail: Sarah.beesley@imail.org Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: To identify research priorities in the management, pathophysiology, and host response of coronavirus disease 2019 in critically ill patients. Design: The Surviving Sepsis Research Committee, a multiprofessional group of 17 international experts representing the European Society of Intensive Care Medicine and Society of Critical Care Medicine, was virtually convened during the coronavirus disease 2019 pandemic. The committee iteratively developed the recommendations and subsequent document. Methods: Each committee member submitted a list of what they believed were the most important priorities for coronavirus disease 2019 research. The entire committee voted on 58 submitted questions to determine top priorities for coronavirus disease 2019 research. Results: The Surviving Sepsis Research Committee provides 13 priorities for coronavirus disease 2019. Of these, the top six priorities were identified and include the following questions: 1) Should the approach to ventilator management differ from the standard approach in patients with acute hypoxic respiratory failure?, 2) Can the host response be modulated for therapeutic benefit?, 3) What specific cells are directly targeted by severe acute respiratory syndrome coronavirus 2, and how do these cells respond?, 4) Can early data be used to predict outcomes of coronavirus disease 2019 and, by extension, to guide therapies?, 5) What is the role of prone positioning and noninvasive ventilation in nonventilated patients with coronavirus disease?, and 6) Which interventions are best to use for viral load modulation and when should they be given? Conclusions: Although knowledge of both biology and treatment has increased exponentially in the first year of the coronavirus disease 2019 pandemic, significant knowledge gaps remain. The research priorities identified represent a roadmap for investigation in coronavirus disease 2019. Drs. Coopersmtih and De Backer are cochairs of the committee who contributed equally to 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). Dr. Coopersmith is past president of the Society of Critical Care Medicine. Dr. Antonelli is immediate past president of European Society of Intensive Care Medicine and received consulting fees from Toray, Intersurgical, and Fisher & Paykel and unrestricted research grants from GE and Estor. Dr. Bauer is a consultant for Wolters Kluwer, and he received funding from Wolters Kluwer. Dr. Deutschman is past president of the Society of Critical Care Medicine scientific editor for Critical Care Medicine, consultant for Enlivex and Lowell Therapeutics; his institution received funding from National Institute of General Medical Sciences; he received funding from the Society of Critical Care Medicine, Elsevier, Enlivex, Sage Therapeutics, and La Jolla Pharmaceuticals; and he received support for article research from the National Institutes of Health (NIH). Dr. Evans disclosed that she serves as the cochair of the Surviving Sepsis Committee and as the adult Surviving Sepsis Campaign Guidelines for the management of sepsis and septic shock. Dr. Ferrer received funding from MSD, Pfizer, and Gilead. Dr. Kesecioglu is president of the European Society of Intensive Care Medicine. Dr. Kissoon is the pediatrics guidelines cochair of the Surviving Sepsis Committee. Dr. Martin-Loeches received honoraria from MSD, Gilead, and Aspen. Dr. Nunnally is Treasurer of the Society of Critical Care Anesthesiologists. Dr. Prescott is the sepsis lead for a Michigan statewide sepsis quality improvement initiative sponsored by Blue Cross Blue Shield of Michigan, and his institution received funding from Agency for Healthcare Research and Quality, the Department of Veterans Affairs, and the NIH, and she disclosed government work. Dr. Rhodes is the adult guidelines cochair of the Surviving Sepsis Committee and a member of the Executive Committee. Dr. Talmor received speaking fees from Hamilton Medical, Clew, and Mindray. Dr Tissieres is president of the European Society of Pediatric and Neonatal Intensive Care, is the pediatrics guidelines cochair of the Surviving Sepsis Committee, and has received consulting fees or research grant from Baxter, bioMerieux, Sanofi. Dr. DeBacker is past president of the European Society of Intensive Care Medicine and has received consulting fees from Fresenius Kabi. The remaining authors have disclosed that they do not have any potential conflicts of interest. Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: Individualizing a target mean arterial pressure is challenging during the initial resuscitation of patients with septic shock. The SEPSISPAM trial suggested that targeting high mean arterial pressure might reduce the occurrence of acute kidney injury among those included patients with a past history of chronic hypertension. We investigated whether the class of antihypertensive medications used before the ICU stay in chronic hypertensive patients was associated with the severity of acute kidney injury occurring after inclusion, according to mean arterial pressure target. Design: Post hoc analysis of the SEPSISPAM trial. Setting: The primary outcome was the occurrence of severe acute kidney injury during the ICU stay defined as kidney disease improving global outcome stage 2 or higher. Secondary outcomes were mortality at day 28 and mortality at day 90. Patients: All patients with chronic hypertension included in SEPSISPAM with available antihypertensive medications data in the hospitalization report were included. Measurements and Main Results: We analyzed 297 patients. Severe acute kidney injury occurred in 184 patients, without difference according to pre-ICU exposure to antihypertensive medications. Patients with pre-ICU exposure to angiotensin II receptor blockers had significantly less severe acute kidney injury in the high mean arterial pressure target group (adjusted odd ratio 0.24 with 95% CI [0.09–0.66]; p = 0.006). No statistically significant association was found after adjustment for pre-ICU exposure to antihypertensive medications and survival. Conclusions: Our results suggest that patients with septic shock and chronic hypertension treated with angiotensin II receptor blocker may benefit from a high mean arterial pressure target to reduce the risk of acute kidney injury occurrence. Drs. Demiselle and Asfar designed the study. Drs. Demiselle and Lemerle collected data in hospitalization reports. Drs. Demiselle and Seegers performed statistical analysis. Drs. Demiselle, Seegers, Guitton, Ricard, Radermacher, and Asfar drafted the article. Drs. Meziani, Grelon, Megarbane, Anguel, Mira, Dequin, Gergaud, Weiss, Legay, Le Tulzo, Conrad, Robert, Gonzalez, Guitton, Tamion, Tonnelier, Bédos, Van Der Linden, Vieillard-Baron, Mariotte, Pradel, Lesieur, Ricard, Hervé, du Cheyron, and Helms included patients in the SEPSISPAM trial and helped to have access to hospitalization reports. All the authors have revised and approved the final version of the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). The SEPSISPAM trial was supported by the French Ministry of Health. Dr. Weiss perceived consultant fees from Med-Day Pharmaceuticals outside of the scope of this article. Dr. Dequin’s institution received funding from Angers University Hospital, the French Ministry of Health, Abionic, Atox Bio, Sphingotec GMBH, Adrenomed, Medspace, Aridis, Merck, Combioxin, GSK, Med-Immune, Genentech INH, Rev-Immune, Faron, Kenta, and Tigenix, and he received support for article research from the French Ministry of Health. Dr. Gonzalez disclosed work for hire. Dr. Teboul received funding from Getinge/Pulsion. Dr. Radermacher’s institution received funding from Deutsche Forschungsgemeinschaft and the German Ministry of Defense. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: piasfar@chu-angers.fr Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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.